Wyoming Sensory Biology COBRE

总结 COBRE第二阶段的目标是促进和开展高质量的科学研究， 在怀俄明州了解人类感觉系统和相关疾病。的主要作用 该中心将支持和指导初级研究人员的发展，以进行感官研究 系统功能和功能障碍。这份行政补充文件的目的是为了增进我们对 神经病理性疼痛和神经退行性变的研究。氧化剂和其他 压力导致神经元中的蛋白质错误折叠，最终导致细胞死亡，但是特定的触发器，靶点， 氧化应激的下游效应仍未被充分研究。在项目1中，张博士将研究 以芽殖酵母为模型的应激诱导神经退行性疾病的细胞和分子基础 系统酵母菌具有多种内源性朊病毒蛋白，它们与人类朊病毒蛋白具有显著的相似性 朊病毒的氨基酸组成和表型传递。酵母朊病毒的某些序列元件 类似于人类淀粉样蛋白的区域。研究表明，分子伴侣，特别是热休克， 热休克蛋白（HSPs）在蛋白质错误折叠和朊病毒聚集中起关键作用。项目1将侧重于角色 热休克蛋白在防止蛋白质错误折叠，朊病毒形成和聚集。在项目2中，Nair博士将探索 连接引起神经病理性疼痛和神经变性的细胞内和细胞外应激源的机制 糖尿病周围神经病变（DPN）。目前，DPN的治疗选择，影响从30%到50%， 在所有糖尿病患者中，是非常有限的。此外，DPN的病因仍然不确定。氧化应激， 促炎细胞因子和异常蛋白酶活性共同对神经元施加压力。初步 来自Nair博士实验室的数据表明，与糖尿病相关的氧化应激导致了 强半胱氨酸蛋白酶组织蛋白酶K（CTSK），可导致细胞凋亡。基因敲除 CTSK可抑制小鼠的伤害反应行为。项目2旨在了解CTSK在DPN中的作用。在 项目3，Gomelsky博士将开发创新的光遗传学工具，使我们能够询问 过度活跃的MMPs和组织蛋白酶。由于CTSK已被证明可以调节MMP 9的作用， 设计近红外光控制的光遗传学系统iMMP 9和iCTSK，用于抑制特定的 具有高时空分辨率的体内蛋白酶将作为研究蛋白酶在 神经性疼痛和其他神经元疾病。总的来说，拟议的项目解决了我们 了解导致神经性疼痛和神经变性的细胞内和细胞外应激源， 这可能为改进诊断和治疗铺平道路。重要的是，研究问题 团队项目中提出的建议与母公司COBRE奖励和当前正在追求的目标不同， 奖励个人调查员，确保团队项目补充现有工作，而不是 复制它们。

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.