DESCRIPTION (provided by applicant): The long-term objective of this application is to elucidate the role of mTOR signaling in Charcot-Marie-Tooth 1A (CMT1A) disease onset and progression. In particular, we will focus on the potential contribution of aberrant mTOR activity to the dedifferentiation/dysmyelination of Schwann cells that is the hallmark of CMT, and in complementary studies, examine the potential of rapamycin as a novel therapeutic strategy in CMT1A in vivo. The misexpression of myelin proteins is a characteristic feature of most inherited neuropathies. Signaling pathways are activated in response to myelin protein misexpression; these are likely to contribute to the Schwann cell pathology in these disorders but remain incompletely characterized. Previous results strongly suggest that overexpression of PMP22 in CMT1A leads to mTOR activation which, in turn, results in Schwann cell dedifferentiation. Thus, inhibition of mTOR with rapamycin rescues myelination in a tissue culture model of CMT1A. These results indicate mTOR activation is necessary to induce Schwann cell dedifferentiation in CMT1A; it is not known whether it is sufficient. The three specific aims proposed further seek to characterize the role of mTOR in Schwann cell dedifferentiation in CMT1A. In particular, aim one will determine if activation of mTOR is sufficient to induce Schwann cell dedifferentiation and demyelination. Aim two will investigate how PMP22 overexpression results in activation of the mTOR pathway and subsequent Schwann cell dedifferentiation. Aim three will examine the effects of rapamycin treatment of PMP22 transgenic overexpressing rats, a model of CMT1A. CMT1A is the most common inherited neuropathy, affecting 1 in 2500 people; currently, there are no effective therapeutics for this disorder. These studies should provide important new insights into the signaling pathways activated in CMT, in particular mTOR, and determine the potential of rapamycin as a novel therapeutic strategy in CMT1A in vivo. PUBLIC HEALTH RELEVANCE: PROJECT NARRATIVE Charcot-Marie-Tooth 1A (CMT1A) is the most common inherited neuropathy, affecting 1 in 2500 people; currently, there are no effective therapeutics for this disorder. We have identified a novel therapeutic target for CMT1A. If awarded this fellowship, we would utilize a well characterized murine model of CMT1A to apply our therapeutic strategy in vivo and elucidate the molecular mechanisms responsible for disease onset and progression. By identifying the pathways responsible for Schwann cell dedifferentiation, our work may have wide-ranging applications in the development of treatments for other inherited peripheral neuropathies.

PROJECT NARRATIVE Charcot-Marie-Tooth 1A (CMT1A) is the most common inherited neuropathy, affecting 1 in 2500 people; currently, there are no effective therapeutics for this disorder. We have identified a novel therapeutic target for CMT1A. If awarded this fellowship, we would utilize a well characterized murine model of CMT1A to apply our therapeutic strategy in vivo and elucidate the molecular mechanisms responsible for disease onset and progression. By identifying the pathways responsible for Schwann cell dedifferentiation, our work may have wide-ranging applications in the development of treatments for other inherited peripheral neuropathies.