Identification of small molecules that can overcome CNS myelin inhibition

University Of Michigan At Ann Arbor, Ann Arbor MI

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Abstract

DESCRIPTION (provided by applicant): Myelin-associated inhibitors in the central nervous system (CNS) limit functional recovery after stroke or spinal cord injury. Blocking the function of the myelin-associated inhibitor NogoA promotes axon growth and plasticity, and results in enhanced functional recovery after stroke or spinal cord injury in rodent models. The goal of this proposal is to develop a high throughput protein-protein interaction screen to identify chemical compounds that can circumvent the inhibitory action of myelin-derived proteins on axon growth and neuronal plasticity. Specifically, we propose to identify selective small molecule inhibitors of the Plenty of SH3 (POSH) protein complex. Our studies demonstrate that NogoA signals to the POSH scaffold to inhibit axon outgrowth, and that neurons deficient in POSH function are refractory to myelin inhibition. Compounds that target the POSH complex are hypothesized to circumvent the inhibitory action of myelin associated proteins, facilitating axon outgrowth and plasticity in the CNS. We propose: 1) To develop a high throughput flow cytometry assay for quantitating POSH complex protein-protein interactions;2) To screen chemical libraries for selective small molecule inhibitors of the POSH complex;and, 3) To test candidate compounds for efficacy in neuronal cell culture models. The identification of selective small molecular inhibitors of POSH action will provide chemical tools to study POSH function and signaling events regulated by myelin-associated inhibitors in neurons in culture. In addition, inhibitors of the POSH complex will provide a starting point for the development of new therapies directed at promoting axon growth and plasticity to enhance functional recovery after stroke or spinal cord injury. PUBLIC HEALTH RELEVANCE: The regenerative and plastic capacity of the central nervous system (CNS) of higher vertebrates is greatly diminished after the onset of myelination. Strategies to promote functional recovery after spinal cord injury or stroke will need to overcome this inhibitory environment of the CNS. These studies are expected to identify selective small molecule compounds that relieve inhibition of CNS myelin on axon growth and neural plasticity, provide chemical tools to further our understanding of the myelin based inhibitory signaling pathways in cells and in vivo, as well as serve as a starting point for therapeutic drug development.