Sarm1 Pathway: New Therapeutic Targets in Neuropathy

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 DESCRIPTION (provided by applicant): The goal of this mentored career development award is to facilitate the PI's transition to independence as a physician-scientist with clinical expertie in neuromuscular medicine and a research emphasis in the molecular mechanisms of peripheral neuropathies. The proposed research, to be conducted under the guidance of primary mentor Dr. Aaron DiAntonio, will evaluate Sarm1 as a therapeutic target in neuropathies, identify other components of the Sarm1 axon destruction pathway and investigate how components downstream of Sarm 1 interact with it and each other to control axon degeneration (AxD). AxD is a prominent feature of most neuropathies and also occurs early in several other neurodegenerative disorders. However, no treatments currently exist that target axonal degeneration specifically. Recently, it was discovered that knocking down the Toll-like receptor adaptor Sarm1 dramatically protects axons from acute degeneration after axotomy. This clearly implicates Sarm1 as an effector in the pathway mediating acute AxD and gives hope that inhibition of Sarm1 and its downstream components may be useful therapeutically. However, a major limitation for translating Sarm1 into candidate therapeutics is our lack of knowledge of the molecular mechanisms that underlie its axodestructive actions. In view of these considerations we propose a research program guided by the following specific aims: 1) Determine, using behavioral, electrodiagnostic and histopathological methods, if Sarm1 knock out ameliorates vincristine induced neuropathy 2) Identify proteins that function downstream in the Sarm1 destructive pathway using a candidate-based suppressor screen in dorsal root ganglion neurons. 3) Investigate the functional interactions of Sarm1 and a recently identified suppressor (Fbxo7) using biochemical, anatomical, and molecular genetics methods in combination with live cell imaging. The proposed experiments are expected to reveal previously unknown mechanisms of AxD and identify new therapeutic targets in neuropathies. The research training supported by the requested funds will parallel the PI's clinical focus in neuromuscular medicine and provide a skill set and possibly new therapeutic agents for translating basic science discoveries into treatment strategies relevant to patients with neuropathies and possibly other neurodegenerative diseases.