Exploring the role of kinases and phosphatases in Charcot-Marie-Tooth neuropathy.

Peripheral neuropathies (PNs) affect 3-4% of the old (>55 years). Often, the disease manifests as result of stress (e.g. diabetes or chemotherapy). There are also hereditary forms of neuropathies. Patients experience altered sensations and pain in hands/feet as well as orthopedic and coordination problems. Hereditary PNs start in the first two decades of life. Among them Charcot- Marie Tooth disease (CMT) is the most frequent subtype which is currently, like all other PNs, incurable. Patients are only treated to relieve symptoms, leaving them ultimately severely disabled. The development of a therapy, requires a better understanding of the molecular mechanisms underlying CMT. I propose to test the role of a regulatory cellular signaling mechanisms (phosphorylation) in the CMT-etiology. As an expert in the biology of neuropathy and phosphorylation, I will perform my work in a lab specialized in CMT-genetics. My idea that phosphorylation might be critical for CMT results from a genetic screen utilizing the CMT-fly model established by my host lab. To verify these results, I have engineered human CMT-cell lines. By analyzing their signaling state via (phosphor)- proteomics, I will pinpoint the best molecular targets for future therapies. The advantage of focusing on phosphorylation is the detailed knowledge of phosphor-pathways and their modulators. I will genetically test putative drug-targets in vivo laying the foundation for the first therapy specific for CMT. -

Keywords:CHARCOT-MARIE-TOOTH DISEASE

Disciplines:Genetics, Systems biology, Molecular and cell biology