Wyoming Sensory Biology COBRE

摘要 科布雷第二阶段的目标是促进和开展高质量的科学研究，以促进我们的 了解怀俄明州的人类感觉系统和相关疾病。的一个主要角色 该中心旨在支持和指导初级研究人员的发展，以从事感官研究 系统功能和功能障碍。这本行政副刊的目的是增进我们对 由细胞内和细胞外应激源引起的神经病理性疼痛和神经变性。氧化和其他 应激导致神经元中的蛋白质错误折叠，最终导致细胞死亡，但特定的触发因素、靶点、 而氧化应激的下游影响仍未得到充分研究。在项目1中，张博士将调查 以芽殖酵母为模型的应激性神经退行性疾病的细胞分子基础 系统。酵母具有几种与人类有显著相似之处的内源性普恩蛋白 酪蛋白在氨基酸组成和传播中的表型。酵母蛋白基因的某些序列元件 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 蛋白质(HSPs)在蛋白质错误折叠和Prion聚集中起着关键作用。项目1将侧重于角色 热休克蛋白在防止蛋白质错误折叠、Pron形成和聚集方面的作用。在项目2中，奈尔博士将探索 细胞内外应激源引起神经病理性疼痛和神经变性的机制 糖尿病周围神经病变(DPN)。目前，DPN的治疗方案影响30%至50% 在所有糖尿病患者中，这一比例极其有限。此外，DPN的病因仍不确定。氧化应激， 促炎细胞因子和异常的蛋白水解酶活性共同对神经元施加压力。初步 奈尔博士实验室的数据表明，与糖尿病相关的氧化应激会导致基因上调 半胱氨酸蛋白酶组织蛋白酶K(CTSK)的活性，可导致细胞凋亡。基因敲除 CTSK可减轻小鼠的致病行为。项目2旨在了解CTSK在DPN中的作用。在……里面 项目3，Gomelsky博士将开发创新的光遗传工具，使我们能够询问 神经疾病中过度活跃的基质金属蛋白酶和组织蛋白酶。由于CTSK已被证明可以规范MMP9的行为， 设计一种近红外光控光遗传系统，iMMP9和iCTSK，用于抑制特定的 具有高时空分辨率的体内蛋白水解酶将成为研究蛋白水解酶在体内的作用的有力工具 神经病理性疼痛和其他神经性疾病。总体而言，拟议的项目解决了我们在 了解导致神经病理性疼痛和神经变性的细胞内外应激源， 潜在地为改进诊断和治疗铺平了道路。重要的是，研究问题 团队项目中提出的建议与家长Cobre奖和当前正在进行的计划不同 奖励个人调查人员，确保团队项目补充现有的工作，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.