Wyoming Sensory Biology COBRE

怀俄明州感官生物学 COBRE

基本信息

批准号：
10852744
负责人：
Qian-Quan Sun
金额：
$ 90.79万
依托单位：
UNIVERSITY OF WYOMING
依托单位国家：
美国
项目类别：
财政年份：
2017
资助国家：
美国
起止时间：
2017-09-01 至 2027-07-31
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10852744
关键词：
2,4-Dinitrophenol Address Administrative Supplement Affect Amino Acids Amyloid Animals Apoptosis Attenuated Award Behavior Biological Models Biology Caspase Cathepsins Cell Death Cell Death Induction Cell Line Cellular Stress Cellular biology Centers of Research Excellence Collaborations Complement Data Development Diabetes Mellitus Diagnosis Disease Elements Engineering Ensure Etiology Fostering Functional disorder Genetic Glucose Goals Heat shock proteins Human Hyperactivity Individual Induction of Apoptosis Inflammation Inflammatory Knock-out Laboratories Light Link MMP9 gene Matrix Metalloproteinases Mentors Methodology Molecular Molecular Biology Molecular Chaperones Mus Nerve Degeneration Neurodegenerative Disorders Neuroglia Neurons Neuropathy Neurosciences Oxidative Stress Parents Pathogenesis Patients Peptide Hydrolases Performance Peripheral Nervous System Diseases Phase Phenotype Play PrP Prions Protease Inhibitor Research Research Personnel Resolution Role Saccharomycetales Sensory Stress System Testing Up-Regulation Wyoming Yeasts cathepsin K cytokine diabetic extracellular improved in vivo innovation insight interest member neuron loss optogenetics pain sensitivity painful neuropathy prevent protein misfolding sensory system spatiotemporal stressor tool transmission process yeast prion

项目摘要

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.

概括 COBRE 第二阶段的目标是促进和开展高质量的科学研究，以推动我们的进步了解怀俄明州的人类感觉系统和相关疾病。一个主要角色是该中心旨在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失调。本行政补充文件的目的是增进我们的理解由细胞内和细胞外应激源引起的神经性疼痛和神经变性。氧化及其他压力会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、目标、氧化应激的下游影响仍未得到充分研究。在项目1中，张博士将研究使用芽殖酵母作为模型研究应激诱导的神经退行性疾病的细胞和分子基础系统。酵母拥有多种内源性朊病毒蛋白，与人类有显着相似之处朊病毒的氨基酸组成和表型传递。酵母朊病毒的一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，尤其是热休克蛋白质（HSP）在蛋白质错误折叠和朊病毒聚集中发挥着关键作用。项目 1 将重点关注角色热休克蛋白在防止蛋白质错误折叠、朊病毒形成和聚集方面的作用。在项目 2 中，奈尔博士将探索连接细胞内和细胞外应激源的机制，导致神经病理性疼痛和神经变性糖尿病周围神经病变（DPN）。目前，DPN 的治疗方案影响了 30% 至 50% 在所有糖尿病患者中，这种情况极为有限。此外，DPN 的病因仍不确定。氧化应激，促炎细胞因子和异常蛋白酶活性共同对神经元施加压力。初步的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上调有效的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 可减轻小鼠的伤害行为。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，使我们能够探究神经病中过度活跃的 MMP 和组织蛋白酶。由于 CTSK 已被证明可以调节 MMP9 的作用，设计近红外光控制的光遗传学系统 iMMP9 和 iCTSK，用于抑制特定的具有高时空分辨率的体内蛋白酶将成为研究蛋白酶在神经性疼痛和其他神经元疾病。总体而言，拟议的项目解决了我们在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，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 奖项和当前所追求的目标不同奖励个人研究者，确保团队项目补充现有的努力，而不是重复它们。