Mechanisms of neuroprotection in diabetic peripheral neuropathy

项目总结

Project Summary Diabetic peripheral neuropathy (DPN) is the most common cause of peripheral neuropathy in the developed world and cause significant morbidity with associated healthcare expenses. It affects up to 30% of all diabetic patients and reduces the quality of life of patients. The primary defect in DPN that results in patient symptoms is the distal degeneration of peripheral axons, also known as dying-back axonopathy. Although some symptomatic therapies exist, these are only partially effective and currently there is no treatment that halts or reverses the axon degeneration or disease progression apart from strict diabetic control. DPN may progress even in patients with good diabetic control, emphasizing the complex biology of axon degeneration in diabetic patients with associated metabolic syndrome. Although the underlying mechanisms of dying-back axon degeneration in diabetes is likely to be complex and involve multiple impaired molecular pathways, the eventual degradation of axonal components leading to axonal degeneration includes key molecular players shared with programmed axon degeneration. These include NAD+ synthesizing enzyme, NMNAT2 and NAD+ degrading enzyme, Sarm1. Activation of Sarm1 is required for axonal degeneration but how this activation is regulated is still under investigation. Several years ago, we took a different approach to developing therapeutic targets to prevent axonal degeneration in peripheral neuropathies. Instead of targeting a specific pathway, we started with a phenotypic drug screen to prevent axon degeneration and identified SF3B2, a component of the spliceosome complex as playing a key role in preventing axon degeneration caused by chemotherapy drugs. Our preliminary studies indicate SF3B2 is upstream of Sarm1 activation and offer an alternative therapeutic target that may spare potential off-target side effects of Sarm1 inhibition. The overarching hypothesis to be tested in this application is that molecules that play a key role in programmed axon degeneration are important in development and progression of diabetic peripheral neuropathy and that targeting them with a novel drug may offer new therapeutic opportunities. We will test these hypotheses by i) examining the effect sensory neuron specific genetic deletion Sarm1 and SF3B2 on development of peripheral neuropathy in high fat diet (HFD) model of type 2 diabetes; ii) identifying mechanism of action of SF3B2 and iii) testing the efficacy of EQ-6 in the HFD model of DPN.