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Final Report Summary - POLYMODALITY (Molecular and pharmacology study of the transient receptor potential channel TRPV1)

The ability of an organism to sense and react to painful stimuli is essential for its survival. In mammals, distinct somatosensory neuronal cells in the trigeminal (TG) and dorsal root (DRG) ganglia, known as nociceptors, are responsible for the detection of environmental and endogenous noxious stimuli. In comparison with other primary sensory neurons, nociceptors have a unique ability to detect and respond to a wide range of both physical and chemical stimuli. As such, they are equipped with a great diversity of transduction mechanisms, allowing them to react and integrate distinct types of challenges. Thus, a fundamental part of understanding somatosensation, nociception, and pain is determining the mechanisms through which nociceptors detect and integrate various stimuli. In this study, we focus on determining the mechanism of action of a member of the TRPV (vanilloid) subfamily, the heat and capsaicin (the ‘hot’ ingredient in chili peppers) receptor TRPV1. Both genetic and pharmacological studies have demonstrated that this receptor is an essential component of the cellular mechanism through which injury evokes acute and inflammatory pain. TRPV1 is a nonselective cation channel, and is a transducer that can respond to insults of several types: physical (e.g., noxious heat, ≥42°C) and chemical (e.g., capsaicin, protons, and animal peptide toxins). Although the pivotal contribution of TRPV1 to pain sensation has been established by many studies, our knowledge of the molecular mechanism of its action is still lacking. In particular, the mechanisms that governs its unique ability to be activated by different noxious stimuli (i.e., polymodality). As part of this study, we determined the mechanism of TRPV1 activation by different modalities, and found they activate the receptor in distinct pattern. Moreover, our results indicated that the agonist’s physical and chemical properties determine the evoked activation mechanism. Thus, our results point to a yet undescribed activation mechanism of this polymodal receptor. More so, our findings contributes to a better understandings of the molecular machinery involves in initial detection of noxious stimuli and the subsequent transduction of the information to higher centers.
TRPV1 is a pivotal component of the pain pathway, and its activation is associated with initiation and maintaining of acute, inflammatory, and neuropathic pain. Inflammatory pain accompanies many diseases, such as rheumatoid arthritis, osteoarthritis, autoimmune diseases, inflammatory bowel diseases, pelvic inflammatory disease, transplant rejection, and cancer pain. These forms of pain severely and tragically hamper the life in those suffer from them. Thus, identifying specific regions and allosteric regulatory mechanisms by which TRPV1 is activated will facilitate the rational design of analgesics drugs to relieve inflammatory and chronic pain in human patients, which is currently an unmet medical need. Thus, our findings propose that development of agents for different binding sites of the receptor will be concluded differently. Thus, we provide a region map of the receptor for activation and/or inhibition of the pain pathway. Furthermore, our study will contribute to the understanding of the activation mechanism of pain receptors in general, and will therefore benefit the development of analgesics drugs targeting other such receptors (e.g. TRPA1).
One of the goals set in the research proposal was the establishment of a functional lab with multiple modules: molecular biology, biochemical and electrophysiological. Indeed, I was able to establish a lab that has all of these modules, and to date two papers where already published as direct result of this grant. My lab includes three PhD students, a M.Sc. student, two undergraduate students, a postdoc, and a technician. Furthermore, I established several collaborations in Israel, Europe and USA with world leading scientists. I presented our studies in several national and international meetings, including invited talks and poster presentations. I recruited external grants dedicated to the research conducted in my lab. In addition to teaching Pharmacology for undergraduate pharmacy students, I launched two new courses, one on the function of ion channels (which is my field of expertise), and the second one on scientific writings. Both courses are mainly for graduate students, although undergraduate in their last year of studies are also encouraged to participate.

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Life Sciences
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