CMT and distal SMAs

Hereditary motor and sensory neuropathies (Charcot-Marie-Tooth disease) are the most common hereditary neurological disorder affecting approximately 1 in 2,000 individuals.  Axonal CMTs are allelic with distal SMAs and result in progressive weakness of distal limb and at times bulbar musculature.   

Identification of novel causes of CMT/dSMA.

In order to futher understand normal motor neuron and peripheral nerve biology and pathological events that cause neurodegeneration, we aim to identify novel genetic causes of spinal muscular atrophies (SMAs) and Charot-Marie Tooth diseases (CMTs). To date, we have identified mutations in the genes encoding the p150Glued subunit of dynactin (a microtubule motor protein

important for retrograde motor

axonal transport), Fbox38 (a

transcription factor), transient

receptor potential vanilloid 4

(TRPV4-a cation channel), and

JAG1 (a Notchligand).  Because

TRPV4 is a surface expressed

ion channel, it represents an

attractive targetfor therapeutics.

We have demonstrated that

TRPV4 mutations cause a gain

of channel function and increased intracellular calcium concentrations. 

Understanding molecular and cellular mechanisms of TRPV4 mediated neuronal dysfunction and degeneration. We are currently studying cellular, drosophila, and mouse models of mutant TRPV4 disease in order to characterize the normal and pathological roles of TRPV4 in the nervous system in vivo and investigate whether TRPV4 small molecule antagonists can mitigate disease. We have confirmed that TRPV4 mutations cause a gain of channel function in a Drosphila model and demonstrated an important role for TRPV4 in neural vascular endothelial cells.  We are currently studying the role of TRPV4 neural vascular ECs in several novel mouse models of disease and in iPSC-derived cells.