Grant: Project Grant

Objective Diabetic sensory neuropathy and chemotherapy-induced peripheral neuropathy (CIPN) are neurodegenerative diseases characterized by loss of nerve fibers in the skin. Both diseases cause significant pain and eventually lead to sensory loss. The impact of these diseases on human health is enormously damaging and there are no therapies. Our recent work has uncovered an endogenous signaling pathway in neurons that negatively modulates nerve fiber growth of sensory neurons. The neurotransmitter, acetylcholine, is produced by sensory neurons and skin cells and activates the muscarinic receptor. Inhibiting the function of the receptor in sensory neurons using selective drugs or by genetically removing the gene significantly increases nerve fiber growth. We propose a "cholinergic constraint hypothesis" describing a role for acetylcholine in restricting growth of nerves within the skin. The general objectives are: a) To suppress the muscarinic receptor pathway to repair nerve endings damaged by diabetes or anti-cancer agents. b) To determine the mechanism whereby receptor blockade enhances nerve growth with a focus on a role in control of calcium signaling and mitochondrial function. Impact statement The proposed studies have a strong translational potential if successful. Our work with topical delivery of muscarinic blocking drugs (already FDA-approved for another indication) has progressed to a point where one small phase 2 clinical trial is complete and additional studies are envisaged for early 2019 for treatment of diabetic neuropathy. A company, WinSanTor, Inc., has been set up and will oversee delivery of this plan. This proposal, if funded, will enable the work to broaden in scope and permit this therapeutic approach to be performed in a wide range of distal dying back neurodegenerative diseases.