genetics Archives - USF Health News https://hscweb3.hsc.usf.edu/blog/tag/genetics/ USF Health News Wed, 10 Nov 2021 00:49:38 +0000 en-US hourly 1 https://wordpress.org/?v=6.5.3 TEDDY study compares characteristics of children diagnosed with type 1 diabetes before and after age 6 https://hscweb3.hsc.usf.edu/blog/2021/10/20/teddy-study-compares-characteristics-of-children-diagnosed-with-type-1-diabetes-before-and-after-age-6/ Wed, 20 Oct 2021 22:16:09 +0000 https://hscweb3.hsc.usf.edu/?p=35242 Development of autoimmunity at an early age associated with more aggressive form of the disease in genetically susceptible children, a USF Health-led study suggests TAMPA, Fla. (Oct. 21, […]

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Development of autoimmunity at an early age associated with more aggressive form of the disease in genetically susceptible children, a USF Health-led study suggests

TAMPA, Fla. (Oct. 21, 2021) — New findings from the international The Environmental Determinants of Diabetes in the Young (TEDDY) study add to the growing body of evidence indicating that type 1 diabetes is not a single disease. The presentation and, perhaps, cause of autoimmune diabetes differs among genetically high-risk children, the research suggests.

In a cohort study published July 22 in Diabetologia, lead author Jeffrey Krischer, PhD, director of the Health Informatics Institute at the USF Health Morsani College of Medicine, and TEDDY colleagues compared the characteristics of type 1 diabetes diagnosed in children before vs. after age 6.  The paper’s senior author was Beena Akolkar, PhD, of the National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK).

“Our results underscore the importance of taking into account the age at development of multiple autoantibodies when evaluating risk factors for progression to a diabetes diagnosis,” said lead author Dr. Krischer, a Distinguished University Health Professor and co-chair for the National Institutes of Health-funded TEDDY consortium. “When the changing picture of autoantibody presentation is considered, it appears type 1 diabetes at an early age is a more aggressive form of the disease.”

In type 1 diabetes, a misdirected immune response attacks and destroys insulin-producing beta cells in the healthy person’s pancreas – a process occurring over months or many years. Four autoantibodies directed against the pancreatic β-cells — glutamic acid decarboxylase autoantibody (GADA), insulin autoantibody (IA), insulinoma-associated-protein-2 autoantibody (IA2-2A), and zinc transporter 8 autoantibody (ZnT8A) – are thus far the most reliable biological indicators of early type 1 diabetes, before symptoms appear. Not all children who test positive for one or more autoantibodies progress to a diagnosis of type 1 diabetes, which requires lifelong administration of insulin to control blood sugar levels and reduce health complications.

Over the last decade, TEDDY researchers have learned more about how the order, timing and type of autoantibodies can help predict which genetically susceptible children are most likely to get type 1 diabetes as they age.

For this multisite study in the U.S. and Europe, the researchers analyzed data from 8,502 children, all at genetically high risk for developing autoimmunity and type 1 diabetes. The children were followed from birth to a median of 9 years. Over this period, 328 study participants (3.9%) progressed from a presymptomatic stage in which autoantibodies first appeared in their circulating blood (signaling initial autoimmunity) to the onset of symptomatic type 1 diabetes.

Study lead author Jeffrey Krischer, PhD, directs the USF Health Informatics Institute and is co-chair for the National Institutes of Health-funded TEDDY consortium.

Half of the 328 participants (2.0%) were diagnosed before age 6, while the other half (1.9%) developed diabetes between ages 6 and 12. The aim was to determine whether the younger group diagnosed with type 1 diabetes differed from the older group, which would suggest that a different form of type 1 diabetes emerges in children as they grow older.

Among the findings:

  • As expected, TEDDY participants who progressed to diabetes between ages 6 and 12 were more likely to have first-appearing autoantibodies to the pancreatic enzyme glutamic acid decarboxylase (GAD autoantibodies), while first-appearing insulin autoantibodies (IA antibodies) were much more common in younger children developing the disease.
  • The rate of progression to type 1 diabetes was slower if multiple (two or more) autoantibodies appeared after age 6 than if they were present before age 6.
  • The significant association of country of origin with diabetes risk found in the younger group declined in the older group. Conversely, the link between certain genotypes and a higher likelihood of developing diabetes significantly increased in the older children.
  • Among children 6 and older with multiple autoantibodies, family history did not appear to play a role in whether the child progressed to type 1 diabetes.

“Much of the observed differences in the relationship between genes and environmental exposures can be explained by the age at appearance of autoantibodies,” Dr. Krischer said. “That is important, because it means factors linked with diabetes risk need to be conditioned on age to be properly understood. There may be different environmental exposures occurring at different ages that trigger autoimmunity, or the same environmental trigger may act differently at different ages.”

The research was funded by grants from the NIDDK and several other NIH institutes, JDRF, and the Centers for Disease Control and Prevention (CDC); and supported in part by NIH/NCATS Clinical and Translational Science Awards.

 

 



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Saulius Sumanas uses versatile fish model system to study how regulation of gene activity affects blood vessel growth https://hscweb3.hsc.usf.edu/blog/2021/03/10/saulius-sumanas-uses-versatile-fish-model-system-to-study-how-regulation-of-gene-activity-affects-blood-vessel-growth/ Wed, 10 Mar 2021 22:26:29 +0000 https://hscweb3.hsc.usf.edu/?p=33615 The research could help identify new drugs or advance tissue regeneration for vascular diseases, including brain aneurysms USF Health’s Saulius Sumanas, PhD, focuses on understanding both normal blood […]

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The research could help identify new drugs or advance tissue regeneration for vascular diseases, including brain aneurysms

Saulius Sumanas, PhD, associate professor of pathology and cell biology, studies the critical regulation of blood vessel formation in health and disease. He joined the USF Health Heart Institute in August 2020. | Photo by Allison Long, USF Health Communications

USF Health’s Saulius Sumanas, PhD, focuses on understanding both normal blood vessel formation and what goes wrong with the critical regulation of these vessels when disease develops.

Arteries and veins and the tiny capillaries connecting them are responsible for transporting blood to organs and tissues throughout the body, among other functions. The molecular factors responsible the growth and health of these blood vessels are important in nearly all diseases.

Dr. Sumanas joined USF Health in August 2020 as an associate professor of pathology and cell biology at the USF Health Heart Institute. He moved his laboratory to Tampa from Cincinnati Children’s Hospital Medical Center and the University of Cincinnati College of Medicine. He says he was attracted by the Heart Institute’s strong cardiovascular research group, with its emphasis on bridging basic science and clinical translational research to create new therapies.

To help define molecular and cellular abnormalities that occur when blood vessels networks do not work as they should, the Sumanas laboratory uses zebrafish to model human diseases, including intracranial (brain) aneurysms associated with cardiovascular risk factors.

“Too little vascular supply can promote some diseases like chronic heart and kidney failure, whereas uncontrolled vascular growth can incite diseases like cancer. For regenerative medicine, the intention is to grow new heart tissue, but there is a simultaneous need to grow new blood vessels to supply nutrients to stem cells that are creating the new heart muscle,” said Samuel Wickline, MD, professor of cardiovascular sciences and director of the USF Health Heart Institute.

“The zebrafish model established by Dr. Sumanas will be a powerful resource to tease out the molecular signals that either need to be enhanced or suppressed to combat these diseases, or to regenerate new functional heart tissue.”

At least 70% of the genes in humans are like those in zebrafish. Zebrafish models, such as the one established by the Sumanas laboratory, can be used to identify molecular signals that need to be enhanced or inhibited to combat diseases, or to regenerate functional heart tissue. | Photo by Allison Long, USF Health Communications

An efficient system for modeling human disease

At least 70% of the genes in humans are like those in zebrafish, and 84% of genes associated with human disease have a zebrafish counterpart.

“The mechanisms regulating vertebrate blood vessel growth are remarkably conserved (across species) from zebrafish to humans,” Dr. Sumanas said. “Even drugs that suppress new blood vessel formation, like the vascular endothelial growth factor (VEGF) inhibitors used to treat tumors in patients, work the same way in zebrafish as they do in humans.”

Other attributes make zebrafish, a member of the minnow family, an efficient model system well suited for scientists searching for genetic clues to disease, including during early blood vessel formation. The fish reproduce and mature rapidly, they are easy to maintain in large numbers for accelerated gene function studies and drug screening, and their eggs are fertilized outside the body. Since zebrafish embryos are virtually transparent, researchers can watch their development in real time. They observe with light and fluorescent microscopy how blood vessels grow from progenitor cells and how the organism’s anatomy and physiology changes when DNA with human genetic mutations is introduced and expressed in the zebrafish.

Ultimately, the Sumanas team hopes to apply what they learn about vascular genetics and developmental biology from this versatile model system to discover new, more targeted treatments for several cardiovascular diseases.

“For example,” Dr. Sumanas said, “now that we have a fish model that shows an increased incidence of hemorrhages (brain bleeds) and defects similar to those of humans with intracranial aneurysms, we can use this model to quickly screen various chemical compounds.” That will help researchers identify if any of the most promising compounds can prevent or reduce the incidence of hemorrhages caused by some intracranial aneurysms. The lead compounds can then be further tested and refined as potential drug candidates for patients.

USF Health’s Saulius Sumanas, PhD, with some of the team members In his laboratory: (L to R) Sanjeeva Metikala, PhD, research associate; Shane Alexander, undergraduate researcher; and Diandra Rufin, biological scientist | Photo by Allison Long, USF Health Communications

Searching for genetic causes of brain aneurysms

While he was a faculty member at Children’s Hospital Medical Center and the University of Cincinnati College of Medicine, Dr. Sumanas collaborated with a group of clinicians looking for genetic variants (mutations) that predispose several members of the same families to intracranial aneurysm, a bulge that forms in a weak area of a blood vessel in the brain. If the aneurysm leaks blood or ruptures, it can cause brain damage and be fatal. (President Joe Biden underwent surgery at age 45, while he was a Delaware senator, to correct a life-threatening brain aneurysm at the base of his brain.)

The Cincinnati group performed functional genomic sequencing of individuals from several families affected by intracranial aneurysms, and subsequently Dr. Sumanas used a zebrafish model to study the functional role of the gene collagen XXII (COL22A1). The researchers demonstrated that COL22A1 plays a role in maintaining blood vessel stability, and their work suggests that mutations in COL22A1 may be a cause of intracranial aneurysms in humans.

Another study led by Dr. Sumanas, reported last year in Nature Communications, discovered that a deficiency of one gene, Etv2, in zebrafish embryos can convert vascular endothelial progenitor cells into skeletal muscle. (Progenitor cells are stem cell descendants that can further differentiate into specialized cell types belonging to the same tissue or organ.) The study concluded that functioning Etv2 actively suppresses these progenitors from differentiating into muscle cells, thereby keeping the cells committed to their vascular destiny: developing into the endothelial cells that are critical building blocks of all blood vessels.

Besides deepening the understanding of complex processes required to differentiate stem cells and grow healthy blood vessels, the work has potential for regenerative therapies, Dr. Sumanas said.

 

Discovering a gene critical to vascular regulation

Zebrafish embryos are virtually transparent, so researchers can observe blood vessel development in real time. | Image courtesy of Saulius Sumanas, PhD

As a postdoctoral fellow at UCLA in 2006, Dr. Sumanas was the first to identify Etv2 function in forming blood vessels in any organism – and has since studied this gene extensively. “There is a lot of interest in Etv2, because it functions as a master regulator of vascular development and allows you to create vascular endothelial cells in a (petri) dish,” he said. “Eventually, we may be able to grow healthy endothelial cells that could be used to repair damaged blood vessels or contribute to tissue or organ regeneration.”

More research is needed to determine precisely how Etv2-regulated vascular “cell fate” is modified to form skeletal muscle cells, but that too could be clinically useful, Dr. Sumanas said. “It may allow a way to make extra muscle, which could be important for treating different types of muscular dystrophies.”

Dr. Sumanas received his PhD degree in biochemistry, molecular biology, and biophysics from the University of Minnesota. He subsequently completed a postdoctoral fellowship in cell and developmental biology at UCLA. He was a faculty member for 13 years in the Division of Developmental Biology at Cincinnati Children’s Hospital Medical Center/University of Cincinnati before joining USF Health. His awards include a 2004 Vascular Biology Training Grant and a Scholars in Oncologic Molecular Imaging Training Award, both from UCLA; a March of Dimes Basil O’Connor Starter Scholar Research Award; and a Perinatal Institute Pilot Research Award, to name a few.

Dr. Sumanas’ research on the role of collagen COL22A1 in intracranial aneurysms and vascular stability is funded by a four-year $1.8 million grant from the National Institutes of Health’s National Heart, Lung, and Blood Institute. He has published more than 40 peer-reviewed papers in the journals such as Nature Communications, Developmental Cell, Development, Arteriosclerosis, Thrombosis, and Vascular Biology and others. He has served on the NIH Cardiovascular Disease and Differentiation review panel (2021), and as an American Heart Association study section member (2014-2020).

An 11-year-old Saulius Sumanas (left), as he appears in a scene from a 1986 TV miniseries titled “Sesiolikmeciai,” which translates to “Sixteen Year Olds” in Lithuanian. He played a younger version of a teenager appearing in later episodes of the World War II drama.

Something you may not know about Dr. Sumanas

Dr. Sumanas was born in Kaunas, Lithuania. At age 11, he was cast as an actor in the first episode of a dramatic TV mini-series titled “Sesiolikmeciai,” which translates to “Sixteen Year Olds” in Lithuanian. He played the similar-looking, younger boy version of a teenage character who lives through Nazi Germany’s occupation of Lithuania (then the Soviet Union) during World War II.

Dr. Sumanas performed other roles in some amateur theater groups as an undergraduate and postdoctoral student, but his pursuit of a biomedical research career did not waver. “Acting was a lot of fun, but my passion for science was stronger,” he said.

Photo by Allison Long | USF Health Communications

 



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Autoantibody order, timing helps predict genetically susceptible children most likely to get type 1 diabetes https://hscweb3.hsc.usf.edu/blog/2020/10/28/autoantibody-order-timing-helps-predict-genetically-susceptible-children-most-likely-to-get-type-1-diabetes/ Wed, 28 Oct 2020 19:19:09 +0000 https://hscweb3.hsc.usf.edu/?p=32751 USF Health-led TEDDY analysis focuses on development of multiple distinct autoantibodies targeting insulin-producing cells, from initial autoimmunity to symptomatic disease TAMPA, Fla. — Children with multiple islet autoantibodies […]

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USF Health-led TEDDY analysis focuses on development of multiple distinct autoantibodies targeting insulin-producing cells, from initial autoimmunity to symptomatic disease

Girl learning about glucose reading.


TAMPA, Fla. —
Children with multiple islet autoantibodies – biological markers of autoimmunity – are more likely to progress to symptomatic type 1 diabetes (T1D) than those who remain positive for a single autoantibody.

Now, new findings from The Environmental Determinants of Diabetes in the Young (TEDDY) study in the U.S. and Europe show that detailed information about the order, timing and type of autoantibodies appearing after the first autoantibody can significantly improve prediction of which children are most likely to progress to type 1 diabetes more rapidly.

The TEDDY analysis was published in the September 2020 issue of Diabetes Care.

“A better understanding of distinct autoantibody spreading is important, because it will allow us to identify at-risk children earlier in the disease process,” said the study’s lead author Kendra Vehik, PhD, a professor of epidemiology at the University of South Florida Health (USF Health) Morsani College of Medicine’s Health Informatics Institute. “That means while children are still asymptomatic, we can start to look at interventions and strategies that may reduce, delay or stop the progression of type 1 diabetes.”

While antibodies are molecules produced by the body’s immune system to detect and destroy specific viruses, bacteria and other harmful substances, autoantibodies are antibodies that target a person’s own healthy tissue. In the case of T1D, a misdirected autoimmune response attacks the pancreas and gradually destroys the organ’s insulin-producing beta cells.

Without the hormone insulin the body cannot regulate its blood sugar levels, which can cause serious, long-term medical complications such as cardiovascular disease, nerve and kidney damage, and vision loss. Children (and adults) with T1D must monitor their dietary intake and exercise and take insulin injections, or use an insulin pump, daily to help control their blood sugar levels.

“Physically and psychologically, it’s a very burdensome disease that needs to be managed every day over a lifetime,” Dr. Vehik said.

Kendra Vehik, PhD, an epidemiologist at the USF Health Informatics Institute, led the TEDDY analysis.

For this TEDDY analysis, eligible children with increased genetic risk for T1D, were followed every three months, from the age of 3 months up to 15 years, for the development of a first-appearing autoantibody directed against pancreatic insulin-producing cells: glutamic acid decarboxylase antibody (GADA), insulin autoantibody (IAA), or insulinoma-associated-protein-2 autoantibody (IA2-2A). The researchers also looked for the subsequent appearance of a second autoantibody and further progression to T1D. Zinc transporter 8 autoantibody(ZnT8A) was only measured in children who developed an IAA, GADA, or IA-2A. These four different autoantibodies are so far the most reliable biological indicators of early T1D, before symptoms become apparent.

Of the 608 study participants – all testing positive for either a first-appearing IAA or GADA — more than half (336) developed a second autoantibody. Furthermore, 53% of these 336 children with a second antibody progressed to T1D within about 3.5 years.  Only about 10% of the 272 children testing positive for a single autoantibody at the end of the follow-up for this study (Dec. 31, 2019) had transitioned to T1D.

Among the key study findings:

  • All study participants had high-risk genotypes for T1D. However, those increased-risk children who also had a parent or sibling with T1D were more likely to develop a second-appearing autoantibody than those without a family history.
  • The younger the child at the time they tested positive for a first autoantibody, the greater their risk for developing a second autoantibody. Conversely, the risk for T1D decreased if the first autoantibody appeared when the child was older.
  • Children testing positive for a second autoantibody, regardless of the type, had at least a five-fold increased risk of progressing to T1D, compared to children who stayed single autoantibody positive. IA-2A, as a second autoantibody, conferred the highest risk, compared with GADA, IAA, or ZnT8A.
  • Risk of progression to T1D was influenced by how quickly the second autoantibody appeared. Emergence of a second autoantibody within a year of the first doubled the risk of progression to T1D. Children’s likelihood of developing T1D declined as the months between the first and second-appearing autoantibodies increased.

Doctor instructing young type 1 diabetes patient about how to use an insulin pump

Better stratifying the risk of progression from the start of autoimmunity to symptomatic disease could help diagnose T1D earlier and offers the opportunity to prevent diabetic ketoacidosis (DKA) and its serious complications by educating parents to watch for early signs, Dr. Vehik said.

“For instance, if a clinician knows that a young child testing positive for IA-2A as their second-appearing autoantibody will be at a higher risk to more rapidly progress to type 1 diabetes, they can reduce the risk of symptomatic onset of disease. Clinicians can also educate the parents about the early signs of disease, such as, weight loss, extreme thirst, more frequent urination, or other DKA symptoms,” she said. “If that happens, the parents will know they should get their child to a doctor or hospital as soon as possible.”

Specific antibody risk profiling can also help identify those at-risk children most likely to benefit from recruitment for T1D prevention trials, Dr. Vehik added.

Dr. Vehik next plans to build upon a previous TEDDY study linking viral behavior with T1D diabetes to test whether prolonged viral infections may environmentally trigger the transition from first- to second-appearing islet autoantibodies in children genetically susceptible to diabetes.

The recently published autoantibody analysis by Dr. Vehik and TEDDY colleagues was funded by National Institute of Diabetes and Digestive and Kidney Diseases grants. USF Health’s Dr. Jeffrey Krischer is the study chair and director of the data coordinating center for the NIH-sponsored TEDDY international multicenter study.

ABOUT TEDDY
The Environmental Determinants of Diabetes in the Young (TEDDY) study is a longitudinal, multinational study examining genetic-environmental causes of type 1 diabetes (T1D). The study follows children at high genetic risk for T1D from birth to 15 years of age at 6 clinical centers in the U.S. and Europe. TEDDY is funded by the National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK), National Institute of Allergy and Infectious Diseases (NIAID), Eunice Kennedy Shriver National Institute of Child Health and Human Development (NICHD), National Institute of Environmental Health Sciences (NIEHS), Centers for Disease Control and Prevention (CDC), and JDRF. More information can be found on the TEDDY study website.



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Brendan Walker studies brain changes driving addictive behaviors https://hscweb3.hsc.usf.edu/blog/2019/12/17/brendan-walker-studies-brain-changes-driving-addictive-behaviors/ Tue, 17 Dec 2019 15:38:11 +0000 https://hscweb3.hsc.usf.edu/?p=30146 The USF Health neuroscientist aims to translate his research on kappa opioid receptors into personalized treatments for alcoholism and other addictive disorders //www.youtube.com/watch?v=FRU0TCpvsuo When USF Health neuroscientist Brendan […]

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The USF Health neuroscientist aims to translate his research on kappa opioid receptors into personalized treatments for alcoholism and other addictive disorders

//www.youtube.com/watch?v=FRU0TCpvsuo

When USF Health neuroscientist Brendan Walker, PhD, was a teen in California at the height of the 1980s crack epidemic, several of his friends who were top intellects and accomplished athletes grew increasingly dependent on cocaine and alcohol. Some died from their addictions.

The painful loss of friends he grew up with started his journey toward a research career seeking to understand the neurobehavioral systems that drive addiction. “I wondered what could be so powerful about drugs of abuse, including alcohol, that would take over someone to the point where they lost their life,” he said.

Dr. Walker, a professor in the Department of Psychiatry and Behavioral Neurosciences, joined the USF Health Morsani College of Medicine in June 2019.

Brendan Walker, PhD, in his laboratory at the USF Health Department of Psychiatry and Behavioral Neurosciences. Dr. Walker’s group focuses on the long-lasting negative reinforcement aspects of heavy alcohol use in the brain, which can make giving up drinking difficult.

Backed by a five-year, $1.79-million R01 grant  from the National Institutes of Health, National Institute on Alcohol Abuse and Alcoholism, his laboratory primarily studies the role of kappa opioid receptors in the transition to alcohol dependence. His long-term goal is to turn those discoveries into targeted medications and gene therapies for addictive disorders leading to devastating social, occupational and health consequences.

Historically many researchers have paid more attention to the positive reinforcement effects of alcohol and drugs — particularly the interaction in the brain of peptides known as endorphins with the mu opioid receptors. Endorphins are natural “feel good” chemicals (neurotransmitters) that can relieve stress, boost mood and produce a feeling of euphoria.

Excessive drinking takes a toll on society as a whole, costing an estimated $249 billion a year, according to the Centers for Disease Control and Prevention.

Dr. Walker and his USF Health team focus on a less studied opioid receptor called the kappa receptor.

They examine what happens in the brain circuitry when the alcohol-induced release of “feel bad” peptides called dynorphins activate kappa opioid receptors. Their preclinical research has shown that abnormal regulation of this dynorphin/kappa-opioid receptor system through excessive drinking can stimulate dysphoria associated with negative emotional states like depression and anxiety, as well as impaired motivation, judgement and decision-making, Dr. Walker said.

“It’s hard to stop drinking once a person achieves a particular pattern of heavy use,” he said. “By blocking some of the dysphoria that drives excessive alcohol use, we’re incorporating a new modality that may achieve better long-term success in stopping alcoholism.”

Dr. Walker with his research team

Brain changes and maladaptive behaviors

Although Dr. Walker’s research centers on alcohol use disorders, the work has relevance for a wide range of addictions.

“Our group and others have shown that the progressive dysregulation that occurs in the brain can extend to all drugs of abuse, whether it be opiates like heroin, or psychostimulants like cocaine and nicotine,” he said. “Whatever the addictive disorder, many of the exact same physical changes happen in the brain to cause a person to adapt in ways that perpetuate self-harm.”

One example of this “maladaptive behavior” is impulsively choosing to consume more alcohol for instant gratification, rather than abstaining from drinking to attain long-term goals. “All these different drugs of abuse activate brain reward systems 50 to 100 times more (powerfully) than anything natural can,” Dr. Walker added. “Instead of having to go out and achieve a long-term goal to get that feeling of euphoria, an individual can inject, smoke or drink something to quickly activate those systems.”

Senior biological scientist Rong (Jennifer) Wang

Many individuals start using alcohol or drugs to get the euphoric ‘feel good’ effects. But the brain normally prefers a set point that balances the highs and lows of mood, so problems arise with misuse, Dr.  Walker said. “The more you artificially create this euphoria, the more intensely the brain fights back by creating dysphoria to equalize the system.”

As alcohol dependence escalates, those who quit drinking in an attempt to stay sober no longer experience the heightened “up” state of euphoria – but all the negative feelings of dysphoria, the “down” state, remain and become more pronounced, he added.  “So, they frequently end up drinking again to self-medicate the depression and anxiety that occurs during withdrawal.”

A major obstacle to recovery — even months or years after rehabilitation and prolonged abstinence – appears to be physical changes in neurotransmitters and their receptor targets as the brain adapts to drugs of abuse.

“Depending on how long or how intensely someone has used alcohol or other drugs of abuse, the dysregulation of the dynorphin-kappa opioid receptor system can persist long after someone stops using,” Dr. Walker said. “Certain environmental cues, like seeing or smelling something associated with prior misuse, may reactivate the dysphoria and cause a relapse.”

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The “one-two” punch of alcoholism

In a key paper published in Biological Psychiatry (2014) titled “The one-two punch of alcoholism,” Dr. Walker and colleagues demonstrated that the dynorphin-kappa opioid receptor system is dysregulated in the amygdala of rats chronically exposed to alcohol. The brain’s amygdala region is vital for many functions, including regulation of emotional behavior and decision-making.

The researchers discovered that dynorphins and signaling by their target kappa opioid receptors both increased in the amygdala, combining to produce a greater (adverse) effect than normal. This combined upregulation underlies the highly maladaptive behavior that promotes continued drinking to temporarily relieve moodiness, anxiety, depression and other dysphoria symptoms, Dr. Walker said.

In the same study, alcohol-dependent rats in acute alcohol withdrawal started to drink like they were nondependent when pharmacological compounds were administered directly into the amygdala to specifically suppress activation of the kappa opioid receptors. The data contributed by Dr. Walker strongly supported the hypothesis that kappa receptor antagonists (blockers) could be a beneficial treatment target for combatting alcohol dependence — in part by preventing a relapse among patients during and soon after withdrawal.

His preclinical work helped determine that kappa opioid receptors were important for the therapeutic effectiveness of nalmefene, a medicine licensed in the European Union to reduce heavy drinking in alcoholic patients who cannot completely abstain.

Gengze Wei, PhD, scientific researcher

Genetics underlying alcohol dependence

Armed with advanced genetic tools, Dr. Walker’s laboratory has also begun exploring ways that genetic variations may work with environmental cues to regulate the neurobehavior (negative emotions, poor judgement and decision-making) that contributes to excessive drinking and relapse.

His group is comparing changes in kappa-opioid receptor gene expression in various brain regions both in alcohol-dependent rats and in their nondependent counterparts. They expect soon to be able to precisely target subtypes of nerve cells involved in shifting the brain’s circuitry from nondependence to dependence. The USF Health researchers plan to mimic the gene expression changes in nondependent rats to observe if they start drinking like dependent rats. They will also block these genetic variations in dependent rats to try to reverse the alcohol-induced maladaptive behavior.

The ability to safely modify specific genes would treat the underlying neurobehavioral causes of alcohol use disorder – not just its symptoms.

The science isn’t there yet. But, Dr. Walker envisions a time when behavioral screening to identify factors that most motivate a person to abuse alcohol or other drugs could be combined with genotyping to help break the addict’s cycle of dependence.

“If we could profile the major genetic and environmental factors that push an individual to continue excessive use, then we could personalize treatment approaches,” he said. “It could help predict how effective a particular treatment would be for an individual patient — and improve the chances of success.”

Stains of dopamine neurons in the midbrain

A White House early career award 

Dr. Walker came to the University of South Florida from Washington State University, where he was an associate professor of psychology.  He was previously a staff scientist for molecular and integrative neurosciences at the Scripps Research Institute in La Jolla, CA.

Dr. Walker received a PhD in neuroscience and behavior from the University of California, Santa Barbara in 2004, and completed postdoctoral research at the Pearson Center for Alcoholism and Addiction Research at Scripps.

He has received numerous distinguished awards, including the 2011 Presidential Early Career Award for Scientists and Engineers presented by President Barack Obama at the White House. The highly competitive PECASE award recognizes exceptional potential for leadership at the frontiers of scientific knowledge.

Continuously funded by the NIH since 2001, Dr. Walker has authored 36 papers in peer-reviewed journals. He served on editorial boards for Neuropsychopharmacology and Honors in Higher Education and as a grants reviewer for the NIH Molecular Neuropharmacology and Signaling (MNPS) study section. He is a member of the American College of Neuropsychopharmacology, the Research Society on Alcoholism and the Society for Neuroscience. 

The 2011 Presidential Early Career Award for Scientists and Engineers, presented to Dr. Walker at the White House, recognizes exceptional potential for leadership at the frontiers of scientific knowledge.

Some things you may not know about Dr. Walker 

  • Walker and his wife Jennifer Walker, an IRB research compliance administrator at USF, are both certified scuba divers. They look forward to combining scuba diving with sailing along Florida’s Gulf Coast on his family’s Irwin Ketch called “Peregrine.”
  • As a boy in Los Angeles, Dr. Walker hiked to the landmark Hollywood Hills sign overlooking downtown LA, climbing to the top of its white capital letters to take in the view.

-Video by Allison Long, and photos by Freddie Coleman, USF Health Communications and Marketing



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Early life stress plus overexpressed FKBP5 protein increases anxiety behavior https://hscweb3.hsc.usf.edu/blog/2019/06/10/early-life-stress-plus-overexpressed-fkbp5-protein-increases-anxiety-behavior/ Mon, 10 Jun 2019 15:31:47 +0000 https://hscweb3.hsc.usf.edu/?p=28421 A USF Health preclinical study adds to mounting evidence about the interplay between genetics and environment in mental health TAMPA, Fla. (June 10, 2019) – Researchers continue to […]

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A USF Health preclinical study adds to mounting evidence about the interplay between genetics and environment in mental health

TAMPA, Fla. (June 10, 2019) – Researchers continue to dig for molecular clues to better understand how gene-environment interactions influence neuropsychiatric disease risk and resilience. An increasing number of studies point to a strong association between the FKBP5 gene and increased susceptibility to depression, anxiety, post-traumatic stress disorder and other mental health disorders.

Adding to the growing evidence, a new preclinical study by University of South Florida neuroscientists finds that anxiety-like behavior increases when early life adversity combines with high levels of FKBP5 – a protein capable of modifying hormonal stress response.  Moreover, the researchers demonstrate this genetic-early life stress interaction amplifies anxiety by selectively altering signaling of the enzyme AKT in the dorsal hippocampus, a portion of the brain primarily responsible for cognitive functions like learning and memory.

While more research is required, the study suggests that FKBP5 may be an effective target for treating anxiety and other mood disorders.

Heal

USF Health neuroscientists Laura Blair, PhD, (left) study senior author, and Marangelie Criado-Marrero, PhD, lead author.  The monitor displays a cross-sectional image of a mouse hippocampus.

The findings were published June 4 in the International Journal of Molecular Sciences.

“We know that the combination of genetic variations and environmental factors can make people either more or less susceptible to mental illness – even when they experience the same types of trauma,” said senior author Laura Blair, PhD, assistant professor of molecular medicine at the USF Health Byrd Alzheimer’s Center. Postdoctoral scholar Marangelie Criado-Marrero, PhD, was lead author of the study.

“We hypothesized that high FKBP5 and early life stress might yield neuropsychiatric symptoms through altered cellular stress response pathways in the brain.”

In a series of experiments, newborn mice overexpressing human FKBP5 in the forebrain were divided into two groups – one group was exposed to an early life stress (maternal separation), and the other was not.  Two control groups were comprised of stressed and non-stressed mice without brain overexpression of FKBP5. At two months, when the mice were young adults, an elevated-plus maze with open and closed arms was used to test anxiety-like behavior. Compared to all other groups, the mice with high FKBP5 and early life stress showed more anxiety as measured by their tendency to stay within enclosed areas of the maze rather than naturally explore all arms of the maze.

Dr. Criado-Marrero and Dr. Blair

The anxiety effect was more pronounced in the female mice than in males, an observation that aligns with sex differences noted in humans with anxiety disorders, Dr. Blair said.

The researchers also analyzed molecular changes in brains of the mice. They found that AKT signaling, specifically in the dorsal hippocampus, differed depending upon whether or not the mice with high FKBP5 had experienced maternal separation as newborns. AKT signaling – shown to be altered in Alzheimer’s disease and cancer as well as in mental health disorders — affects brain cell survival and metabolism, and the brain’s ability to adapt to new information.

“The AKT signaling pathway was inversely regulated as a result of early life stress. High FKBP5 normally decreases AKT signaling, but when early life stress was added to overexpressed FKBP5 that signaling activity increased,” Dr. Blair said. “Overall, our findings highlight the importance of stress and genes (like FKBP5) in modulating vulnerability to mood disorders and learning impairments.”

The USF Health researchers plan to next study the interaction of high FKBP5 and early life stress in older mice to determine how anxiety is affected by aging.

Slides of mouse neurons were analyzed to look for molecular changes in brain cells that correspond with changes in cognition.

The study was supported by grants from the NIH’s National Institute of Mental Health and National Institute of Neurological Disorders and Stroke.

Anxiety disorders are among the most common mental health conditions in the U.S, affecting 40 million adults, and nearly one in three of all adolescents will experience an anxiety disorder, according to the NIH.

-Photos by Allison Long, USF Health Communications and Marketing



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New drug tested at USF Health Metabolic Clinic is life-changing for patient with PKU https://hscweb3.hsc.usf.edu/blog/2018/06/22/new-drug-tested-at-usf-health-metabolic-clinic-is-life-changing-for-patient-with-pku/ Sat, 23 Jun 2018 00:22:37 +0000 https://hscweb3.hsc.usf.edu/?p=25512 Those helped by the new injectable enzyme therapy, recently approved by the FDA, can safely eat foods that have been forbidden for years Jennifer Mazorra has spent most […]

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Those helped by the new injectable enzyme therapy, recently approved by the FDA, can safely eat foods that have been forbidden for years

Patient Jennifer Mazorra, left, is examined by USF Health’s Dr. Amarilis Sanchez-Valle, a lead researcher for the clinical trial leading to recent FDA approval of the first injectable enzyme therapy for adults with the rare genetic disease PKU.

Jennifer Mazorra has spent most of her life on a diet that severely restricted what she could eat – no meat, fish, eggs, and dairy or other high-protein foods, no artificial sweeteners, and carefully measured amounts of fruits, vegetables and starches.

Mazorra, 35, was diagnosed as a newborn with the rare genetic disease phenylketonuria, or PKU, which prohibits the body from breaking down the amino acid phenylalanine found in all natural proteins. The condition is primarily controlled by a strict diet that can be difficult to maintain. If unmanaged, PKU can damage the nervous system and lead to chronic intellectual, developmental and behavioral problems.

“I was born with PKU – it’s detected by one of the screening tests that all newborns get with a heel stick. As an infant, my mother had to stop breastfeeding and give me a special formula that replaced all the essential amino acids except phenylalanine,” said Mazorra, a nurse practitioner who lives in Naples, Fla. “As a child, she was always aware that every morsel of food that went into my mouth could be tied to my IQ as an adult.”

So Mazorra enthusiastically agreed when USF Health physician Amarilis Sanchez-Valle, MD, of the USF Health Metabolic Clinic, which Mazorra visits routinely to monitor her PKU, suggested a potential option to the lifelong dietary regimen.  In 2014, Mazorra became one of the first participants in a study testing a new injectable drug for adults with PKU.

Dr. Sanchez-Valle directs the USF Health Metabolic Clinic, serving a 14-county service area in Florida, which treats children and adults with all types of hereditary errors in metabolism.

Dr. Sanchez-Valle was a lead investigator of a clinical trial for that injectable enzyme therapy, which had shown promise in breaking down and lowering blood phenylalanine concentrations in those difficult to treat with existing therapy.

The drug, Palynziq, developed by BioMarin Pharmaceutical Inc., was approved in May 2018 by the U.S. Food and Drug Administration.

It took more than a year for Mazorra to start feeling the effects of the drug, and she coped with a milder form of one of its most serious side effects, allergic reaction, by taking an antihistamine before injecting Palynziq.  (All patients treated with Palynziq must be prescribed and instructed how to use auto-injectable epinephrine in case of severe allergic reaction while taking Palynziq.) Pain, sensitivity or itching at the injection site and joint pain are the most common side effects, which typically subside quickly, Dr. Sanchez-Valle said.

The reactions were worth the effort, Mazorra said, when the therapy dropped her phenylalanine levels to normal for the first time in her life and helped her feel healthier.

“My quality of life has been so much better,” she said. “I can think more clearly now.  I’m more energetic and my mood is improved.”

Mazorra, diagnosed with PKU as an infant, has been able to attain phenylalanine levels within normal ranges by taking Palynziq.   She is part of a continuation study investigating differing doses of the new drug.

Dr. Sanchez-Valle, an associate professor of pediatrics who treats children and adults with inherited metabolic disorders from across the university’s 14-county service area, said patients traveled from as far away as Miami over the last few years seeking out a study offering a potential alternative to the PKU diet.

“It’s an exciting time for patients with PKU,” she said. “With this newly approved medication, we’re seeing what we never have before – patients eating normal diets and maintaining levels of phenylalanine within normal ranges.”

Mazorra credits Dr. Sanchez-Valle and her USF Health team for giving her the confidence to become pregnant when others had warned her of the risk of complications from maternal PKU. Babies do not inherit the disorder unless both parents carry the PKU gene, but high levels of phenylalanine in the mother can pass through the placenta as toxins, putting a child at risk for heart problems, cognitive delays and other birth defects.

Mazorra had to stop taking Palynziq weeks before and all during pregnancy, and stick to the strict diet again while battling food cravings.  It wasn’t easy, but with careful monitoring and the help of a metabolic dietitian, she and her husband are now the proud parents of a healthy 8-month-old boy, Sebastian.

Mazorra at home with 8-month-old son Sebastian and husband Gabe. | Photo courtesy of Jennifer Mazorra

Six weeks after giving birth Mazorra resumed Palynziq.  And, she is participating in a continuation study investigating differing doses of the new drug in an expanded population of adult patients to track long-term safety and effectiveness.  Dr. Sanchez-Valle is hopeful that eventually the drug will be studied in teens.

Meanwhile, Mazorra focuses more on her improved quality of life than on long-term effects. Things as simple as enjoying peanut butter toast, a snack off limits to her since childhood.

“I eat peanut butter toast every day now,” she said.

-Photos by Freddie Coleman, USF Health Communications and Marketing

 



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New research discovers genetic variation linked to African Americans with heart failure https://hscweb3.hsc.usf.edu/blog/2018/03/07/new-research-discovers-genetic-defect-specifically-linked-african-americans-heart-failure/ Wed, 07 Mar 2018 16:15:43 +0000 https://hscweb3.hsc.usf.edu/?p=24373 The University of South Florida-led study is another step toward more effective treatments for a population disproportionately affected by this chronic cardiovascular disease TAMPA, Fla. (March 7, 2018) […]

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The University of South Florida-led study is another step toward more effective treatments for a population disproportionately affected by this chronic cardiovascular disease

TAMPA, Fla. (March 7, 2018) — Heart failure is more common, develops earlier and results in higher rates of illness and death in African Americans than in whites.

Now, the first genetic study of its kind to examine the genetic basis of heart failure in African Americans, led by the University of South Florida (USF), Tampa, Fla., has identified a genetic variation linked specifically to heart failure in this population.  The discovery could lead to more precise and effective treatments for African Americans, who are more likely to suffer from a common form of heart failure of unknown cause called idiopathic dilated cardiomyopathy (IDC). IDC is a condition in which the heart weakens, cannot pump blood properly and becomes progressively enlarged.

The National Institutes of Health-funded study was published Feb. 26 in the Journal of Personalized Medicine.

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“We know that this form of heart failure has a worse prognosis in African Americans and does not respond as effectively to most therapies as compared to the same treatments in Caucasian individuals of European descent. Yet, there had never been a genome-wide association study performed exclusively in African Americans,” said senior author and project director Stephen B. Liggett, MD, professor of internal medicine and vice dean for research at the USF Health Morsani College of Medicine.

“We undertook this study because of the severe under-representation of African Americans in these types of trials, and, our idea that the genetic causes might be different in this population,” added Dr. Liggett, a member of the USF Health Heart Institute. “Our genome-wide analysis suggests that is indeed the case, and we may need to develop new drugs to target IDC in African Americans.”

The Genetics of African American Heart Failure consortium examined genetic variations in the genomes of 662 African-American patients recruited from five U.S. academic medical centers:  the University of Cincinnati College of Medicine, Duke University School of Medicine, Johns Hopkins University School of Medicine, University of Maryland College of Medicine, and the Virginia Commonwealth University School of Medicine. All the study participants had no history of heart attacks and were diagnosed with IDC.

The researchers found that a variation in one gene, called CACNB4, could contribute to causing IDC in African Americans.  That same genetic defect has not been found in white patients with IDC. More study is needed, Dr. Liggett said, but CACNB4 plays a key role in regulating calcium signaling important for cardiac muscle contraction, so a variation that interferes with the gene’s function may lead to diminished pumping of blood by the heart.

In addition, variations in other genes suggested an association with IDC in individuals with African-American ancestry.  So, the researchers mapped the biochemical pathways of these 1,000 genes, which created a network indicating the potential action by which these variations lead to IDC, and possible targets for new drugs.  The consortium’s analysis showed that genetic variations in African Americans account for 33 percent of the risk for IDC.   And, many genes forming the pathway map were involved in how calcium regulates the work of heart muscle cells.

Dr. Liggett and his collaborators use various research methods, including examining genetic variation in different ethnic groups, with the aim of understanding how to best devise new drugs for treatment or prevention of heart failure. “Every time we perform these genetic studies, we learn something new and find another piece of the puzzle,” he said, “Ultimately the dissection of this cardiovascular disease will lead to drugs that strike at damaging pathways with a high level of precision, resulting in personalized medicine for heart failure.”

Nearly 6 million people in the United States have heart failure, a figure projected to increase to 8 million by 2030, according to the American Heart Association.  The five-year mortality rates range from 30 to 50 percent, greater than for some cancers.

                                                                         -USF Health-
USF Health’s mission is to envision and implement the future of health. It is the partnership of the USF Health Morsani College of Medicine, the College of Nursing, the College of Public Health, the College of Pharmacy, the School of Physical Therapy and Rehabilitation Sciences, the Biomedical Sciences Graduate and Postdoctoral Programs, and the USF Physicians Group. The University of South Florida, established in 1956 and located in Tampa, is a high-impact, global research university dedicated to student success. USF is ranked in the Top 30 nationally for research expenditures among public universities, according to the National Science Foundation. For more information, visit www.health.usf.edu

 

 

 

 



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Patient perspective helps shape Dr. Rebecca Sutphen’s hereditary cancer research https://hscweb3.hsc.usf.edu/blog/2016/09/25/patient-perspective-helps-shape-dr-rebecca-sutphens-hereditary-cancer-research/ Sun, 25 Sep 2016 18:03:40 +0000 https://hscweb3.hsc.usf.edu/?p=19760 Genetic testing has been available since the mid-1990s to determine if a woman is likely to face one of her gender’s greatest fears: inherited breast and ovarian cancer. […]

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USF Health clinical and molecular geneticist Rebecca Sutphen, MD, has survived breast cancer and melanoma.

Genetic testing has been available since the mid-1990s to determine if a woman is likely to face one of her gender’s greatest fears: inherited breast and ovarian cancer. Yet, questions remain about whether common tests for the genes BRCA1 and BRCA2, which identify mutations that significantly increase a woman’s risk of breast and ovarian cancers, are reaching those who can most benefit and how the information learned from the testing is put to use.

USF Health medical and molecular geneticist Rebecca Sutphen, MD, a breast cancer and melanoma survivor, has broad expertise in genetic conditions affecting both adults and children. She has devoted much of her recent career working with Facing Our Risk of Cancer Empowered (FORCE), the leading national nonprofit advocacy organization for hereditary breast and ovarian cancer, to seek answers that will improve health outcomes of women at high risk for these cancers.

Dr. Sutphen’s research is guided in part by her own experiences as a patient, as well as Big Data’s emerging power to integrate electronic medical information and help build evidence about the effectiveness of clinical care. She emphasizes the need to ensure that patients help shape the investigative process.  In addition to her academic work, she is the chief medical officer of InformedDNA, a national genetic services organization.

The National Cancer Institute estimates only 3 percent of adults with cancer participate in clinical trials, with members of racial and ethnic minorities and low-income individuals particularly underrepresented.

“If research started with the questions that patients want answered, it seems likely there would be more participation in clinical studies, and it would be more obvious to patients how the research is relevant to them,” said Dr. Sutphen, professor of genetics at the USF Health Morsani College of Medicine’s Health Informatics Institute.

Cancer studies still largely focus on determining what treatments contribute to longer life, she said.

“Obviously survival is very important, but patients with cancer often have several options for treatment. What we learn from patients is that they also care about maintaining quality of life – things like the ability to get in their cars and continue to go to the grocery store, or to sleep at night… So, how can we better tailor the treatment options available to match each individual’s preferences?”

COPH sound-icon-png Dr. Sutphen discusses the powerful potential of Big Data.

 

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Dr. Sutphen works out of the Morsani College of Medicine’s Health Informatics Institute led by Jeffrey Krischer, PhD. She is pictured here with clinical research associate Beth Ann Clark, right.

USF helps lead way in BRCA testing and counseling

Dr. Sutphen, proficient in sign language, has a brother and sister who were both born deaf. She says her interest in genetics was sparked as a medical student when she accompanied her sister and her sister’s husband to Johns Hopkins medical genetics clinic for an evaluation of her 2-month-old nephew, also born deaf.

What the family learned about genetics and the probabilities of inheriting certain conditions was informative and fascinating, Dr. Sutphen said. “I saw genetics emerging as a new, growing area of science with the opportunity to impact the lives of people who really need information and can use it in a proactive way to make better decisions for themselves and their families.”

After earning an MD degree from Temple University School of Medicine, she completed a pediatrics residency at All Children’s Hospital in St. Petersburg and a fellowship in human genetics at USF. She is certified by the American Board of Medical Genetics in both clinical and molecular genetics.

In 1995 Dr. Sutphen joined the USF College of Medicine as a faculty member and shortly thereafter became the director of clinical genetics at All Children’s Hospital and at Moffitt Cancer Center.   As BRCA testing became commercially available, she helped USF establish one of the first programs in the state to offer clinical genetic testing and counseling for cancer.

For the first time, a test could identify if a person had inherited a defect in BRCA1 or BRCA2, and therefore tell who was at greater susceptibility for developing breast and ovarian cancer. Also, even if a woman with the inherited mutation never developed cancer herself, she would know she had a 50 percent chance of passing down the mutation, and increased risk, to any offspring.

But many more questions could not be answered. Was the risk the same for everyone who inherited a mutation? Was there a certain age the cancer would be likely to emerge? Could anything modify the risk? Will intensive screening (mammograms, MRIs, ultrasounds) catch a cancer early enough? Should a woman have her breasts or ovaries removed?

“While there was great excitement about the clinical availability of this new testing, there was a huge gap in what we could tell people about their own particular situation and what to do about it,” Dr. Sutphen said.

COPH sound-icon-png Dr. Sutphen comments on engaging patients in the research process.

 

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In the 1990s, Dr. Sutphen helped USF establish one of the first programs in the state to offer clinical genetic testing and counseling for hereditary breast and ovarian cancer.

Meeting begins enduring research collaboration, friendship

Dr. Sutphen began working with Distinguished University Health Professor Jeffrey Krischer, PhD, now director of the Health Informatics Institute, to develop NIH project proposals that would meaningfully address some of these unanswered questions. And in 2004, Dr. Sutphen invited Dr. Sue Friedman, founder and executive director of FORCE, to meet with the USF team to discuss how to best integrate “the patient voice and community” into the group’s hereditary cancer research.

After that initial meeting and learning about USF’s advanced health informatics capabilities, Dr. Friedman said, she quickly drafted a proposal to move her fledging nonprofit organization and family from South Florida to Tampa to work more closely with the USF team.

“When we first started looking at what a collaboration for hereditary breast and ovarian cancer research would look like, we included things like a yearly conference, a patient registry, research grants, writing a book. And, while there have been challenges along the way, in the last 12 years we’ve accomplished a lot of what we dreamed about and continue to build upon it,” Dr. Friedman said. “Aligning with USF has enhanced our organization’s ability to deliver meaningful research to the community, not just in terms of recruiting patients and reporting study results, but to actually help drive the research at every level.”

Along the way, Dr. Friedman, also a breast cancer survivor, and Dr. Sutphen became best friends as well research partners. “Rebecca has been visionary in recognizing the value of including health plan data in the research, and extraordinarily open to bringing in patients as equal stakeholders.”

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Sue Friedman (left), founder and executive director of Facing Our Risk of Cancer Empowered, or FORCE, and USF’s Dr. Sutphen have worked together for the last 12 years. They have become friends who share a commitment to making patients equal stakeholders in driving hereditary cancer research.

COPH sound-icon-png Inherited breast and ovarian cancer community’s influence on personalized medicine.

Research and advocacy join forces

Combining their complementary expertise in research and advocacy, USF Health and FORCE have attracted several highly competitive grants. Currently, Dr. Sutphen is the lead investigator for two national research awards focused on hereditary breast and ovarian cancer research.

  • Impact of BRCA Testing on Newly Diagnosed U.S. Breast Cancer Patients. This landmark study, supported by a $2.8-million NIH RO1 award, is conducted in collaboration with the commercial health insurance plan Aetna. Researchers previously examined de-identified data on thousands of Aetna members across the country who received BRCA testing and surveyed them about factors associated with the use of this testing including genetic counseling services. Now, analyzing de-identified health claims information, Dr. Sutphen and colleagues will track the outcomes of consenting patients with increased risk for breast and ovarian cancer syndrome — including what types of health care professionals the women saw and how the positive genetic test results affected their decisions about managing cancer risk (including preventive treatment options), which patients subsequently were diagnosed with cancer and their medical treatment choices.

 

“To date,” Dr. Sutphen said, “there has been no similar study evaluating the health outcomes of a national sample of women undergoing BRCA testing in community settings.”

 

  • Patient-Powered Research Networks, American BRCA Outcomes and Utilization of Testing Network (ABOUT Network). The project, totaling $2.4-million in support from the Patient Centered Outcomes Research Institute (PCORI) for Phases I and II, continues the work led by USF and FORCE to advance a national patient-centered research network of individuals with hereditary breast and ovarian cancer. The ABOUT Network was created to identify this patient community’s unmet needs, promote their governance in research and focus on the questions and outcomes that matter most to patients and their caregivers. USF’s ABOUT patient-powered research network is one of 20 nationwide participating in PCORI’s initiative to help individuals access their electronic health records data through existing patient portals and share it for research that could improve care for their conditions.

 

“We are establishing mechanisms to allow any patient in the U.S. who has hereditary breast and ovarian cancer to participate in studies relevant to them,” Dr. Sutphen said. “Harnessing the power of Big Data with guidance from patients enables a scale of research never before possible.”

Some early findings have begun to be disseminated. In a study published last year in JAMA Oncology, which attracted national media attention, Dr. Sutphen and co-authors found that most women who underwent BRCA testing did not receive genetic counseling by trained genetics professionals — and lack of physician recommendation was the most commonly reported reason. Yet, those who did get this clinical service before testing were more knowledgeable about BRCA and reported more understanding and satisfaction than women who did not.

This demonstrates gaps in services to be addressed, Dr. Sutphen said, because consultation with a trained genetics clinician is widely available (by phone or in person) and now covered as a preventive health service by most insurers with no out-of-pocket costs to patients.

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COPH sound-icon-png Dr. Sutphen talks about her breast cancer diagnosis.

Researcher confronts breast cancer as patient

Dr. Sutphen was diagnosed with breast cancer in 2008, following a routine mammogram. She was premenopausal and had no family history of cancer.   The radiologist who read her mammogram, a colleague, pulled her out of clinic at the Moffitt Lifetime Cancer Screening Center to alert her to the abnormality on her X-ray. The biopsy confirmed early-stage breast cancer.

“I was shocked,” she said. “I remember the part of the conversation ‘you have cancer,” seeing the doctor’s mouth moving and then not hearing any words after that.”

She called her best friend Sue Friedman, herself a breast cancer survivor, for support and after careful consideration of her treatment options decided to undergo a bilateral mastectomy with reconstruction.   The choice worked well for her, Dr. Sutphen said, but another friend with the same type of breast cancer chose lumpectomy instead.

“The first thing to look at is whether the likelihood for a recurrence of the cancer is the same if you have a lumpectomy or a mastectomy – and if the answer is yes, then beyond that it’s a matter of personal preference,” Dr. Sutphen said. “So, two people can make very different choices, but the right choice for each of them.”

In 2013, after having a “mole that looked different” on her arm checked out, Dr. Sutphen was diagnosed and treated for melanoma.

Her own experiences as a two-time cancer survivor have added perspective to her research, Dr. Sutphen said. “It really emphasized to me just what it’s like to be a patient, how difficult the decisions are to make, and how challenging your emotional state becomes.”

To make the often confusing and complex journey a little easier for patients and their families, Dr. Friedman and Dr. Sutphen collaborated with freelance writer Kathy Steligo on a book titled Confronting Hereditary Breast and Ovarian Cancer: Identify Your Risk, Understand Your Options, Change Your Destiny. They wanted to integrate into one book the latest evidence-based information to help women with cancer-susceptibility genes maximize their long-term survival and quality of life.

“The book was published in 2012, but it’s still 95 percent relevant today,” she said.

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Dr. Sutphen with her daughter Serenity, 11.

Something you may not know about Dr. Sutphen

Dr. Sutphen was named one of the top 10 cancer medical geneticists in the United States in Newsweek’s “Top Cancer Doctors 2015” list. In 2012, she was selected by TEDMED to be the advocate leading its “Shaping the Future of Personalized Medicine” program, part of the Top 20 Great Challenges annual conference.

For many years she enjoyed the scenic adventure of flying paraplanes, or powered parachutes, ultralight aircraft with a motor, wheels and a parachute. But these days Dr. Sutphen prefers remaining on the ground to cheer on daughter Serenity, 11, a horseback rider who competes in barrel racing.

Photos by Eric Younghans, and audioclips by Sandra C. Roa, USF Health Communications

 

 

 

 

 

 



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USF gets $2.3M NIH grant to test new Huntington’s disease therapy merging nanomedicine and gene silencing (Audio) https://hscweb3.hsc.usf.edu/blog/2015/10/23/usf-gets-2-3m-nih-grant-to-test-new-huntingtons-disease-therapy-merging-nanomedicine-and-gene-silencing-audio/ Fri, 23 Oct 2015 22:56:13 +0000 https://hscweb3.hsc.usf.edu/?p=15949 Led by neurologist Dr. Juan-Sanchez-Ramos, the mouse-model study will refine a noninvasive nose-to-brain delivery system using manganese nanoparticles Huntington’s disease (HD) is an incurable, hereditary brain disorder that […]

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Led by neurologist Dr. Juan-Sanchez-Ramos, the mouse-model study will refine a noninvasive nose-to-brain delivery system using manganese nanoparticles

Huntington’s disease (HD) is an incurable, hereditary brain disorder that typically strikes adults in the prime of their lives – gradually affecting movement, mood and mental activity. Involuntary “dance-like” movements, known as chorea, are the most common motor symptoms.  Patients also commonly develop depression and suicidal thoughts, and increasing difficulty with cognitive function makes it difficult to hold a job.

The one drug currently approved by the Food and Drug Administration to alleviate chorea does not change the course of HD.

Dr. Sanchez-Ramos' team was awarded 2.3 million dollar grant

Dr. Juan Sanchez-Ramos, professor of neurology at the USF Health Morsani College of Medicine, is the lead investigator for a new $2.3-million NIH grant studying a non-invasive drug delivery system designed to safely and effectively transport large therapeutic molecules (nucleic acids) from nose to brain.

COPH sound-icon-png Listen to Dr. Sanchez-Ramos talk about a major obstacle to gene therapy.

Where’s the cure?

When the single lethal gene for HD was discovered in 1993, USF Health neurologist Juan-Sanchez, MD, PhD, promised some patients he would help find a cure or effective treatment for the rare, but ravaging, disease that runs in families.   At the time, he was a clinical team member of the U.S.-Venezuela Collaborative Research Project, a landmark study that identified and documented cases of HD and the disease’s progression in a unique community of families in Lake Maracaibo, Venezuela.

While celebrating the gene’s discovery with other clinicians in a village, he asked some HD patients gathered why they were not applauding the breakthrough. They answered with a typical Venezuelan gesture, “¿Y la cura?’” Dr. Sanchez-Ramos said. Translation: “So, where’s the cure?”

The pledge he made early in his career got a major boost last month when USF Health was awarded a new five-year, $2.3 million grant from the National Institutes of Health’s National Institute of Neurological Disorders and Stroke. Principal investigator Dr. Sanchez-Ramos and his team — using a mouse model for Huntington’s disease — will assess and refine a new nanoparticle carrier system they’ve designed to transport therapeutic gene-silencing molecules from the nasal passages to the brain.  The interdisciplinary team includes researchers from the USF Department of Neurology, USF Nanomedicine Research Center, Moffitt Cancer Center and the University of Massachusetts Medical School’s RNA Therapeutics Institute.

Dr. Sanchez-Ramos' team was awarded 2.3 million dollar grant

From left, the USF team of investigators includes Gary Martinez, PhD (Moffitt Cancer Center); Dr. Sanchez-Ramos; Vasyl Sava, PhD; Xiaoyuan Kong; Subhra Mohapatra, PhD; Shijiie Song, MD; and Shyam Mohapatra, PhD. Not pictured are Neil Aronin, MD, and Anastasia Khvorova, PhD, both of the University of Massachusetts RNA Therapeutics Institute.

COPH sound-icon-png Dr. Sanchez-Ramos comments on the nose-to-brain nanocarrier delivery system his team will be studying and refining.

Delivering therapeutic molecules for a global brain disease

“This NIH study will allow us to test exactly how the nanoparticles get from the nose to the brain, how they are disseminated from the olfactory bulb to other parts of the brain, and how long they stay before dissipating,” said Dr. Sanchez-Ramos, professor of neurology and director of the Huntington’s Disease Center of Excellence at the USF Health Morsani College of Medicine.

“We want all parts of the brain to be exposed to these gene silencing molecules, because Huntington’s is a global brain disease; as the disease advances, no part of the brain is spared”.

There is still much work to be done but, if proven successful, the nose-to-brain approach could be used to non-invasively (via nasal spray or drops) deliver all kinds of drugs, including DNA therapy and nerve growth factors, which would otherwise be blocked from entering the brain by the blood-brain barrier.

“It could have applications for modifying a wide range of brain disorders,” Dr. Sanchez-Ramos said.

Gene-silencing technology without neurosurgery

The normal huntingtin gene contains a DNA alphabet that repeats the letters C-A-G as many as 26 times, but people who develop HD have an excessive number of these consecutive C-A-G triplet repeats — greater than 39. The defective gene leads to a toxic huntingtin protein, which appears to play a critical role in nerve cell function.  HD is autosomal dominant, meaning if one parent has a copy of the faulty gene each child’s chance of inheriting the disease is 50 percent. The disease emerges slowly, usually between ages 30 and 50 (average age of diagnosis in the United States is 38), but onset can be earlier or later.  Research suggests that the greater the number of C-A-G repeats the earlier symptoms tend to appear and the faster they progress.

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Gene therapy is not new to HD or other neurodegenerative diseases. In the past, Dr. Sanchez-Ramos said, it primarily involved replacing a missing gene or delivering therapeutic molecules to help enhance cell survival.  More recently, research applications using small interfering RNA, or siRNA, continue to advance gene therapy’s potential use to modulate the expression of genes, including silencing or suppressing overactive genes.

“Researchers have already found that you can silence the Huntington’s disease gene in animal models,” Dr. Sanchez-Ramos said, “but no one has yet delivered these gene-silencing molecules other than surgically — either by stereotaxic injection of viral vectors, or by direct infusion into the brain or cerebrospinal fluid.

“The neurosurgical approach is just not feasible for patients with a chronic illness that gradually encompasses the entire central nervous system.”

Overcoming a major obstacle: the blood-brain barrier 

Preliminary mouse model experiments indicate the unique nanocarrier system designed by the USF researchers will overcome the major obstacle of invasive delivery as well as bypass the blood-brain barrier, a gatekeeper between the blood and brain tissue that selectively filters which molecules can enter the brain.

USF has patent pending for the system, which incorporates manganese-containing nanoparticles that rapidly target brain tissue after simple nasal administration.  The biodegradable nanoparticles encapsulate gene-silencing molecules made to inhibit the activity of the HD gene.

“The system transports the nanoparticles from nose to brain where siRNA (the gene-silencing molecule) is released and triggers the dissolving of messenger RNA so that it cannot go on to produce the abnormal protein that causes Huntington’s disease,” Dr. Sanchez-Ramos said.  “Our approach is promising, reasonable and safe.”

Dr. Sanchez-Ramos' team was awarded 2.3 million dollar grant

Dr. Sanchez-Ramos directs the Huntington’s Disease Society of America Center of Excellence at USF, where he cares for patients, many of whom are enrolled in clinical trials offered through the center. Kristy Yehle, right, participates in Enroll-HD, an international observational study for Huntington’s disease families.

In their series of NIH-supported studies, the USF researchers will visualize and track nose-to-brain transport of the manganese-containing nanoparticles in the mice using magnetic resonance imaging. (The contrast agent safely injected into patients undergoing some MRI tests contains manganese.)

Dr. Sanchez suspects that the nanoparticles may access the deeper regions of the brain through spaces surrounding the brain’s neurons and blood vessels rather than by the olfactory nerves alone, but the experiments will help quantify how the nanocarrier system works.  The study will also evaluate the effectiveness of the gene-silencing molecules in reducing or preventing motor and behavioral symptoms in the HD mice and look for ways to optimize the distribution and dosing.

On the threshold of a cure

The Huntington’s Disease Society of America (HDSA) Center of Excellence at USF, one of the largest regional referral centers in the Southeast, has treated more than 600 patients and their families since earning the HDSA designation more than 10 years ago. Many patients enroll in clinical studies testing investigational drugs and tracking the natural history of the disease in search of biomarkers.

Dr. Sanchez-Ramos' team was awarded 2.3 million dollar grant

Early in his career, while working as part of an international research team in Venezuela, Dr. Sanchez-Ramos promised some patients he would help find a cure or effective treatment for Hurtington’s disease.

At USF’s center, Dr. Sanchez-Ramos listens to their stories about struggling with and overcoming the challenges of living with HD and their determination to live each day to the fullest. The clinician-scientist remembers the promise he made in Venezuela.  He remains optimistic that research by USF and others combining nanomedicine and gene-silencing technology will lead to human trials, and ultimately, effective therapies to prevent HD or delay its progression.

“We’ve found a way to hit this single-gene disease with global symptoms at its source – by knocking out the abnormal gene expression,” Dr. Sanchez-Ramos said.

“I’m more hopeful than ever that we’re on the threshold of a cure for Huntington’s disease.”

Photos by Eric Younghans and animated graphic by Sandra Roa, USF Health Communications and Marketing

 

 



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USF Health, Aetna report on national community-based study of cancer genetic counseling and testing services https://hscweb3.hsc.usf.edu/blog/2015/10/01/usf-health-aetna-report-on-national-community-based-study-of-cancer-genetic-counseling-and-testing-services/ Thu, 01 Oct 2015 14:34:08 +0000 https://hscweb3.hsc.usf.edu/?p=15658 Study identifies gaps in clinical genetic counseling services for women undergoing BRCA genetic testing Tampa, FL (Oct. 1, 2015) – A University of South Florida-led research collaboration with Aetna, […]

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Study identifies gaps in clinical genetic counseling services for women undergoing BRCA genetic testing

Tampa, FL (Oct. 1, 2015) – A University of South Florida-led research collaboration with Aetna, the American Cancer Society and the national non-profit Facing Our Risk of Cancer Empowered (FORCE) today published results from a national study identifying factors and outcomes associated with the use of genetic counseling and testing services for hereditary breast and ovarian cancer in the community setting. The work is reported today in the Journal of the American Medical Association – Oncology and indicates a significant opportunity to increase genetic counseling in community care.

The investigative team for the ABOUT Study (American BRCA Outcomes and Utilization of Testing Study), led by principal investigator Rebecca Sutphen, MD, professor of genetics at the USF Health Morsani College of Medicine, analyzed data from a consecutive series of women whose health care providers requested BRCA testing through the national health insurer, Aetna,  over a one-year period.

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Rebecca Sutphen, MD, professor of genetics at the USF Health Morsani College of Medicine, was principal investigator of the study conducted with Aetna, the American Cancer Society and the national non-profit Facing Our Risk of Cancer Empowered (FORCE).

The guidelines of multiple medical professional societies and health authorities indicate that genetic counseling should precede a decision to undergo BRCA testing.  Despite this guidance, only 36.8 percent of the 3,874 female participants in this study reported receiving genetic counseling from a genetics clinician before BRCA genetic testing.  Importantly, those who received this service demonstrated greater knowledge about BRCA, including risk factors and treatment options. They also expressed greater understanding of and satisfaction with the information they received prior to testing.  The proportion of women receiving the service varied significantly based on the specialty of the provider ordering the test, with the lowest rates among Obstetrician/Gynecologists (12.3 percent).

“The ABOUT Study offers a rare opportunity to study the self-reported experiences of women undergoing testing in the community setting where most people receive their care.  Although we found that most women did not receive genetic counseling by a genetics professional, this is a gap in services that can be addressed,” Sutphen said.

Genetic counseling to support BRCA testing is a preventive service that is covered with no out-of-pocket costs for most women with a family history of breast or ovarian cancer.

“Comprehensive genetic counseling about BRCA mutation testing is important for individuals to understand their cancer risk. The information obtained from genetic counseling empowers individuals as well as current and future generations of their families to make informed decisions about screening, risk reduction, and treatment options,” said Joanne Armstrong, MD, senior medical director and head of Women’s Health for Aetna.

The ABOUT Study was supported by funding from the Aetna Foundation, as well as in-kind support from the American Cancer Society, FORCE and Aetna.

Article Citation:
Armstrong J, Toscano M, Kotchko N, Friedman S, Schwartz MD, Virgo KS, Lynch K, Andrews JE, Aguado Loi CX, Bauer JE, Casares C, Bourquardez Clark E, Kondoff MR, Molina AD, Abdollahian M, Walker G, Sutphen R:  Utilization and Outcomes of BRCA Genetic Testing and Counseling in a National Commercially Insured Population: The ABOUT Study.  JAMA Oncology, Oct. 1, 2015. 

About USF Health
USF Health’s mission is to envision and implement the future of health. It is the partnership of the USF Health Morsani College of Medicine, the College of Nursing, the College of Public Health, the College of Pharmacy, the School of Physical Therapy and Rehabilitation Sciences, and the USF Physician’s Group. The University of South Florida is a Top 50 research university in total research expenditures among both public and private institutions nationwide, according to the National Science Foundation.  For more information, visit www.health.usf.edu

About Aetna
Aetna is one of the nation’s leading diversified health care benefits companies, serving an estimated 46.7 million people with information and resources to help them make better informed decisions about their health care. Aetna offers a broad range of traditional, voluntary and consumer-directed health insurance products and related services, including medical, pharmacy, dental, behavioral health, group life and disability plans, and medical management capabilities, Medicaid health care management services, workers’ compensation administrative services and health information technology products and services. Aetna’s customers include employer groups, individuals, college students, part-time and hourly workers, health plans, health care providers, governmental units, government-sponsored plans, labor groups and expatriates. For more information, see www.aetna.com and learn about how Aetna is helping to build a healthier world. @AetnaNews

 Media contacts:
Anne DeLotto Baier, USF Health Communications, abaier@health.usf.edu or 813-974-3303
Kathy (Betty) Skipper, AETNA Corporate Communications, SkipperB@aetna.com or 404-702-3442



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