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.
Peripheral neuropathy is common, affecting approximately 2% of the population. Peripheral nerve degeneration causes significant sensory and motor disability in patients and is associated with substantial health care costs. Understanding of underlying molecular and cellular mechanisms of neuropathy will accelerate the development of disease-modifying treatments, which are currently lacking. This proposal investigates how mutations of the cation channel transient receptor potential vanilloid 4 (TRPV4) cause peripheral neuropathy in a novel rodent model. The proposed studies have the potential to validate a druggable target for the treatment of TRPV4-induced disease and provide important insights about fundamental mechanisms of peripheral nerve degeneration.
|Sullivan, Jeremy M; Landouré, Guida; Gaudet, Rachelle et al. (2014) Phenotypic spectrum and incidence of TRPV4 mutations in patients with inherited axonal neuropathy. Neurology 83:1991|
|Wong, Ching-On; Chen, Kuchuan; Lin, Yong Qi et al. (2014) A TRPV channel in Drosophila motor neurons regulates presynaptic resting Ca2+ levels, synapse growth, and synaptic transmission. Neuron 84:764-77|