The discoveries of primary sensory receptors that mediate our external senses of smell, touch, taste, and vision were landmark achievements. In contrast, internal sensory systems of the vagus nerve are vastly understudied at a molecular level, with primary sensory receptors unknown in any organ system. The vagus nerve is a major conduit between brain and body that controls feeding behavior, respiration, blood pressure, metabolism, heart rate, nausea, and cough. Mechanosensory and chemosensory transduction mechanisms in the vagus nerve present tremendously important problems in sensory biology. Sensory receptors that detect meal-induced stomach distension, blood pressure at the aortic arch, lung expansion during breathing, irritants that cause cough, or chemotherapeutics that induce nausea are unknown. Understanding how the vagus nerve signals at a molecular level is relevant for a wide range of clinical conditions, including obesity, diabetes, colitis, asthma, nausea, depression, and epilepsy. The goals of this project are to identify primary sensory receptors of the vagus nerve that survey internal organ state. Initial efforts will focus on finding stomach and lung mechanoreceptors as well as aortic baroreceptors, and work could be extended to identify irritant and toxin receptors that evoke cough and nausea. Vagal mechanoreceptors will be identified using a novel in vivo ganglion imaging approach that permits analysis of single neuron responses to internal organ stimuli. In vivo ganglion imaging is compatible with mosaic loss-of-function approaches like RNAi for analysis of gene function. Deconstructing the sensory biology of vagal afferents will reveal basic insights into how autonomic physiology is controlled by the nervous system, and may provide new opportunities for therapy design. This proposal builds on years of foundational work, and is not supportable by traditional funding mechanisms due to the large project scope, the risk associated with receptor-identification studies, and my limited publication record in this new field. So far, our early work in this system has characterized sensory neuron types in different physiological systems (Cell, 2015). Funding would enable new molecular-level efforts to identify primary sensory receptor proteins that detect internal sensory cues.

Public Health Relevance

The vagus nerve is a major body-brain connection that controls autonomic functions of the respiratory, cardiovascular, digestive, and immune systems. Vagus nerve sensory biology remains poorly studied at a molecular level, with receptors unknown that detect meal-induced stomach distension, arterial blood pressure, nausea-inducing toxins, cough-evoking irritants, and lung stretch during tidal breathing. Funding would enable new efforts to understand vagal sensory transduction mechanisms at a molecular level; identifying internal organ sensory receptors of the vagus nerve will transform the field of neurophysiology, and may provide new ways to treat autonomic disease.

Agency
National Institute of Health (NIH)
Institute
National Center for Complementary & Alternative Medicine (NCCAM)
Type
NIH Director’s Pioneer Award (NDPA) (DP1)
Project #
1DP1AT009497-01
Application #
9151840
Study Section
Special Emphasis Panel (ZRG1-BCMB-N (50)R)
Program Officer
Chen, Wen G
Project Start
2016-09-30
Project End
2021-07-31
Budget Start
2016-09-30
Budget End
2017-07-31
Support Year
1
Fiscal Year
2016
Total Cost
$1,186,500
Indirect Cost
$486,500
Name
Harvard Medical School
Department
Anatomy/Cell Biology
Type
Schools of Medicine
DUNS #
047006379
City
Boston
State
MA
Country
United States
Zip Code
02115