Wyoming Sensory Biology COBRE

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SUMMARY The goal of the COBRE Phase II is to foster and conduct high-quality scientific research that advances our understanding of human sensory systems and the related disorders in the state of Wyoming. A major role of the Center is to support and mentor the development of junior investigators to pursue research in sensory system function and dysfunction. The goal of this administrative supplement is to advance our understanding of neuropathic pain and neurodegeneration caused by intra- and extracellular stressors. Oxidative and other stresses cause protein misfolding in neurons, ultimately resulting in cell death, yet specific triggers, targets, and downstream effects of oxidative stress remain underexplored. In Project 1, Dr. Zhang will investigate the cellular and molecular basis of stress-induced neurodegenerative disorders using budding yeast as a model system. Yeast possesses several endogenous prion proteins, which share significant similarities with human prions in amino acid composition and transmission of phenotype. Some sequence elements of yeast prions resemble regions of human amyloids. Studies have shown that molecular chaperones, especially heat shock proteins (HSPs), play critical roles in protein misfolding and prion aggregation. Project 1 will focus on the roles of HSPs in preventing protein misfolding, prion formation and aggregation. In Project 2, Dr. Nair will explore mechanisms linking intra- and extracellular stressors causing neuropathic pain and neurodegeneration in diabetic peripheral neuropathy (DPN). Currently, the treatment options for DPN, which affects from 30 to 50% of all diabetes patients, are extremely limited. Further, the etiology of DPN remains uncertain. Oxidative stress, pro-inflammatory cytokines, and abnormal protease activity collectively impose stress on neurons. Preliminary data from Dr. Nair's laboratory suggest that oxidative stress associated with diabetes causes an upregulation of the potent cysteine protease cathepsin K (CTSK), which can lead to cellular apoptosis. Genetic knockout of CTSK alleviates nocifensive behavior in mice. Project 2 aims to understand the role of CTSK in DPN. In Project 3, Dr. Gomelsky will develop innovative optogenetic tools allowing us to interrogate the role of hyperactive MMPs and cathepsins in neuropathies. As CTSK has been shown to regulate MMP9 actions, engineering a near-infrared light-controlled optogenetic systems, iMMP9 and iCTSK, for inhibition of specific proteases in vivo with high spatiotemporal resolution will serve as potent tools to study the role of proteases in neuropathic pain and other neuronal diseases. Overall, the proposed projects address critical gaps in our understanding of the intra- and extracellular stressors leading to neuropathic pain and neurodegeneration, potentially paving the way for improved diagnosis and treatments. Importantly, the research questions proposed in the Team Project are distinct from those being pursued by the parent COBRE award and current awards of individual investigators, ensuring that the Team Project complements existing efforts rather than duplicates them.