Understanding the sensory nerves involved in protective behaviors may lead to new therapies for respiratory, cardiovascular diseases

Think about the last time you stubbed a toe.

The sensory nerves activated when your toe slammed against a hard object initiated a defensive reflex leading you to withdraw your toe from the source of intense pain. Tom Taylor-Clark, PhD, associate professor in the Department of Molecular Pharmacology and Physiology, likens the pain-induced response to an early warning system that, if working properly, helps us avoid things that can cause damage.

“If you stub your toe once, sure it hurts so much,” he said, “but if you do it repeatedly, eventually you will break your toe.”

In his laboratory at the USF Health Morsani College of Medicine, Dr. Taylor-Clark studies the role of defensive, or nociceptive, sensory nerves in health and disease. Using a combination of electrophysiology, imaging and molecular biology techniques, he investigates how these peripheral nerves, which stimulate organs and penetrate nearly all the body’s tissues, sense their environment. That includes sensory nerve response to external stimuli, like extreme heat or cold, inhaled pollutants or a source of injury, and internal stimuli, such as inflammation, infection or organ damage.

Thomas Taylor-Clark, PhD, an associate professor in the Department of Molecular Pharmacology and Physiology, studies the role of defensive, sensory nerves in health and disease.

“We are interested in understanding the sensory nerves involved in protective behaviors, or defense, because they are the ones that go wrong in disease and injury,” Dr. Taylor-Clark said.

The protective role of airway sensory nerves in cough

His laboratory focuses primarily on the electrical excitability of sensory nerves of the airways. The researchers study the behavior of sensory nerves connecting the lungs with the brainstem, the primitive part of the brain that controls basic body functions such as breathing, swallowing and heart rate. In particular, Dr. Taylor-Clark works with colleagues to better understand the nerves involved in initiating the chronic cough associated with the asthma, a disease characterized by persistent airway inflammation.

Knowing more about how these airway sensory nerves work, including the interface between the conscious and unconscious in the brainstem networks that control cough, is important in understanding how they are disrupted by inflammatory disease. The information could help guide the design of new treatments for unresolved cough and associated symptoms, a major reason people visit primary care providers, Dr. Taylor-Clark said. In addition, better ways to treat cough are important, because for those with a variety of neuromuscular diseases impaired cough can cause an increase in pulmonary infections from aspiration.

Recently, Dr. Taylor-Clark’s team expanded their research to look into how pre-existing cardiovascular disease alters nerve-generated reflexes from the lungs to affect cardiovascular function.

 Dr. Taylor-Clark comments on one aspect of his laboratory’s sensory nerve research.

Stephen Hadley, a senior biological scientist in Dr. Taylor-Clark’s laboratory.

Three research awards totaling more than $2.85 million support their work. The studies are done using cell cultures as well as with the help of transgenic mice that selectively express red fluorescent protein in defensive neurons.

With a grant from the National Heart, Blood and Lung Institute, Dr. Taylor-Clark has investigated the connection between two well-known research findings to determine the downstream effects of mitochondria, the energy producers of the cell, on airway sensory nerve activation. The first finding, he said, was that airway sensory nerves respond to a type of inflammatory signaling that induces potentially damaging oxidative stress. The second was that mitochondria are located right next to signaling receptors in the sensory nerve cells.

“So, we hypothesized that perhaps mitochondria are not there just to produce energy, but to generate signaling,” Dr. Taylor-Clark said. “And we found that mitochondrial signaling activates the sensory nerves specifically by activating chili and wasabi receptors in airways.”

Hot on the trail of wasabi and chili receptors

These receptors for chili peppers (or capsaicin) and wasabi (allylisothiocyanate), officially known as TRPV1 and TRPA1 respectively, are expressed by every single defensive sensory nerve in your body, including those in your tongue, your skin – and your airways (nasal passages, bronchi, larynx). Together the TRPV1 and TRPA1 compounds contribute to involuntary cough reflex.

The USF work linking mitochondrial signaling and airway sensory nerve receptors, triggered by these TRPV1 and TRPA1 molecules that can generate pain as well as heat sensation, resulted in two major papers in the journal Molecular Pharmacology, one in 2013 and another in 2014. A supplementary biophysiological study defining how the wasabi (TRPA1) receptor works was published earlier this year in the Journal of General Physiology.

Above and below: Microscopic images from a transgenic mouse expressing the red fluorescent protein tdTomato  in defensive sensory nerve only.  This crosssection of the lung showing defensive nerve terminals (red)  innervating regions surrounding the small branches of bronchiles, or air tubes (green), within the lungs.

A slice of the brainstem showing central projections of defensive nerves (red) into the medulla, where the nerves transmit signals to brainstem networks to control various involuntary functions like breathing, cough, swallowing, heart rate and blood pressure.

Pollution-induced exacerbation of underlying cardiovascular disease

Another direction of scientific endeavor for Dr. Taylor-Clark is investigating how pre-existing cardiovascular disease may alter normal reflexes from the lungs to affect autonomic regulatory control of the heart. Seed funding from an earlier Morsani College of Medicine Research Office intramural BOOST grant helped his research group obtain a two-year American Heart Association award for this more recent area of research under the auspices of the USF Health Heart Institute.

In preliminary research presented last year at the Experimental Biology Conference, Dr. Taylor-Clark and colleagues reported that hypertensive rats exposed to wasabi, an irritant mimicking the effects of a pollutant like ozone when inhaled into the lungs, experience a much different cardiac response than healthy rats. The heart rate of healthy rats exposed to wasabi slows significantly as a protective mechanism to help slow the distribution of pollutants throughout the body. But given the same exposure, rats with chronic high blood pressure have periods of rapid heartbeats interspersed with a slow heart rate – which can evoke a potentially dangerous abnormal heart rhythm known as premature ventricular contractions.

“So you have a situation where you’ve gone from a healthy (cardiovascular) reflex to an aberrant reflex that may exacerbate pre-existing cardiovascular disease,” he said.

Working with researchers at the University of Florida, Dr. Taylor-Clark is a co-investigator for a recently awarded a three-year, $1.28M grant from the National Institutes of Health Common Fund’s Stimulating Peripheral Activity to Relieve Conditions (SPARC) funding program. The comprehensive project aims to improve maps of the peripheral nervous system —the electrical wiring that connects the brain and spinal cord with the rest of the body – so that more selective and minimally invasive “electroceutical” treatments might be developed for conditions such as heart disease, asthma and gastrointestinal disorders.

 USF’s involvement in NIH project charting defensive airway nerves.

Dr. Taylor-Clark and Stephen Hadley. Recently, Dr. Taylor-Clark’s laboratory expanded its research to look into how pre-existing cardiovascular disease alters nerve-generated reflexes from the lungs to affect cardiovascular function.

Mapping for the future of neuromodulation therapies

The UF-USF multidisciplinary team is focusing on functional mapping of peripheral and central neural circuits for airway protection and breathing.

Using cutting-edge genetic and neurophysiological approaches, they are characterizing the types of defensive airway nerves that control breathing, coughing and heart rate differently and finding where they connect into the brainstem network.

“We are trying to bridge the gap between what has been done (with nerve trafficking) in the lungs and what has been done in the brainstem, and then link them together,” Dr. Taylor-Clark said. “We have transgenic mice that make red fluorescent protein only in their defensive nerves, so now we can chart where targeted nerves are going with superior image quality.”

The team’s overall goal is to advance understanding of the neural pathways underlying respiratory control, laying the groundwork for future neuromodulation therapies to normalize lung function in people at risk.

“If we want to (preferentially) target these therapies for optimal effectiveness, we need to know where all these nerves go and what they do,” Dr. Taylor-Clark said.

Dr. Taylor Clark-received his PhD degree from University College London in 2004. He completed a postdoctoral fellowship at Johns Hopkins University Division of Allergy and Clinical Immunology and served as a medical faculty member at Hopkins for a year before joining USF’s medical school in 2009 as an assistant professor.

Dr. Taylor-Clark is associate chair for research in the Department of Molecular Pharmacology and Physiology. In 2015, he received the Award for Excellence in Teaching from USF’s Graduate PhD Program in Integrated Biological Sciences.

 How mapping neural circuits for airway protection and breathing may lead to novel therapies.

A combination of electrophysiology, imaging and molecular biology techniques are used to study behavior of sensory nerves connecting the lungs with the brainstem.

Some things you might not know about Dr. Taylor-Clark:

• In the mid-1990s, for two years before entering University College London as an undergraduate, he played bass guitar in a band that recorded and performed “very loud rock and roll” as part of the London music scene. These days, with wife Luciana as the audience, Dr. Taylor-Clark jams at home in his living room with daughter Ella, 9, who plays drums.

• Taylor-Clark’s PhD thesis involved a study of how the human nose congests. He measured the internal dimensions of people’s nasal passages with a sonar device at the end of a stick, recruiting family and friends, among others, as study volunteers. He induced sneezing and other symptoms of hay fever by spraying histamine into their nostrils. The shape of the nose and the interaction between nerves and blood vessels in the nose affected air flow and severity of symptoms, he discovered. “While writing the thesis, I began to realize how little was understood about nerves in the airways.”

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 Photos by Eric Younghans, USF Health Communications