A model of TRPV4 channelopathy

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DESCRIPTION (provided by applicant): Peripheral neuropathy results in axonal degeneration of motor and sensory nerve fibers causing muscle weakness and sensory loss. Development of effective therapies has been hampered by incomplete understanding of the underlying molecular and cellular triggers and a lack of druggable therapeutic targets. The discovery that mutations of transient receptor potential vanilloid 4 (TRPV4) cause Charcot- Marie-Tooth disease type 2C marks the first example of an ion channel causing inherited sensorimotor neuropathy. TRPV4 is expressed at the cell surface membrane and several small molecule antagonists have already been developed. In order to further investigate mechanisms of TRPV4-induced neuropathy, we recently developed a novel knock-in mouse model containing the R269C mutation in the endogenous mouse TrpV4 gene. Our preliminary studies of young knock-in mice indicate abnormalities of their peripheral nerve physiology. Using this model, we propose 1) to characterize the spatial and temporal evolution of neuronal dysfunction and degeneration in TRPV4R269C knock-in mice and 2) to test our hypothesis that the R269C mutation causes of gain-of-TRPV4 channel activity in neurons that can be suppressed by TRPV4 antagonists. Together these studies will determine how neuropathy-associated TRPV4 mutations alter TRPV4 function in peripheral neurons, assess the extent to which TRPV4 antagonists may represent a potential therapeutic strategy for patients, and define outcome measures of TRPV4-induced neurodegeneration in mice that can be utilized during future mechanistic and treatment studies.