Elucidation of regulation and function of amyloid-like assemblies

项目摘要 淀粉样蛋白是纤维状蛋白质组装体，被认为在许多严重疾病的进展中起关键作用。 人类疾病，如阿尔茨海默氏症、帕金森氏症和朊病毒疾病。虽然淀粉样蛋白已经 在疾病的背景下，淀粉样蛋白主要被理解为有毒蛋白质沉积物， 开始被认为具有重要的生理功能。为了促进这些功能， 细胞具有未知的机制来调节淀粉样蛋白样组装体的组装和清除。我的研究 愿景是发现和理解细胞调节形成、功能 和淀粉样蛋白的可逆性。这些研究的基础是我们最近的发现，为了控制翻译 在减数分裂过程中，芽殖酵母调节RNA结合蛋白组装成具有许多 淀粉样蛋白的生化特性。从这些研究中获得的知识将导致我们的重要进展， 了解神经退行性疾病的原因，并及时可能导致治疗的机会。 我研究的一个五年目标是了解酵母非凡能力的潜在机制 以有效地调节淀粉样结构的形成和清除。我还将使用在 体外和体内方法来破译RNA的淀粉样蛋白组装如何调节翻译- 结合蛋白芽殖酵母是研究这些过程的一个强有力的实验系统。我的实验室可以很容易地 培养快速同步产生和清除淀粉样蛋白样聚集体的细胞群。 功能性淀粉样蛋白组装体的研究为化学领域提供了令人兴奋的长期机会 筛选和合成生物学。与我们的核心化学筛选设施合作，我的实验室将使用酵母 以筛选和鉴定防止和/或分解淀粉样蛋白样组装的化合物。我还计划设计 基于特异性和抑制作用由以下假设的合成翻译阻遏物： 可互换的蛋白质模块。此外，我将与我部门的其他实验室合作， 哺乳动物和细菌的蛋白质，形成淀粉样蛋白的装配。 这些研究将为理解细胞如何调节的分子基础奠定基础 并加工淀粉样蛋白组装体。尽管进行了大量的研究和开发， 治疗方法一直难以捉摸。它们是治疗神经退行性疾病所必需的， 目前已有预防性治疗。这项工作产生的治疗策略将依赖于我的 将我们从这项研究中获得的发现应用于神经退行性疾病模型的能力。哥伦比亚大学 医学中心和陶布阿尔茨海默氏症和衰老研究所提供了支持框架 和合作的机会来实现这一点。

PROJECT SUMMARY Amyloids are fibrous protein assemblies that are thought to play a critical role in the progression of many severe human diseases such as Alzheimer’s, Parkinson’s, and prion diseases. Although amyloids have been predominantly understood in the context of disease as toxic protein deposits, amyloid-like assemblies are beginning to be recognized as having critical physiological functions. In order to facilitate these functions some cells have unknown mechanisms to regulate assembly and clearance of amyloid-like assemblies. My research vision is to discover and understand the pathways and mechanisms by which cells regulate formation, function, and reversibility of amyloids. The basis for these studies is our recent discovery that in order to control translation during meiosis, budding yeast regulates assembly of an RNA-binding protein into structures that have many biochemical properties of amyloid. Knowledge gained from these studies will lead to important advances in our understanding of the causes of neurodegenerative diseases and in time could lead to therapeutic opportunities. A five-year goal of my research is to understand the mechanisms underlying yeast’s remarkable ability to efficiently regulate both formation and clearance of amyloid-like structures. I will also use a combination of in vitro and in vivo approaches to decipher how translation can be regulated by amyloid-like assemblies of RNA- binding proteins. Budding yeast is a powerful experimental system to study these processes. My lab can easily grow populations of cells that rapidly and synchronously produce and clear amyloid-like assemblies. Investigation of functional amyloid-like assemblies provides exciting long-term opportunities in chemical screening and synthetic biology. In collaboration with our core chemical screening facility, my lab will use yeast to screen and identify compounds that prevent and/or disassemble amyloid-like assemblies. I also plan to design synthetic translational repressors based on the hypothesis that specificity and repression are governed by interchangeable protein modules. Furthermore, I will collaborate with other labs in my department to examine mammalian and bacterial proteins that form amyloid-like assemblies. These studies will lay the foundation for understanding the molecular underpinnings of how cells regulate and process amyloid-like assemblies. Despite much research and development, anti-amyloid preventative therapies have been elusive. They are needed for neurodegenerative diseases in which few if any effective preventative therapies are currently available. Therapeutic strategies resulting from this work will rely on my ability to apply the findings we gain from this study to neurodegenerative disease models. Columbia University Medical Center and the Taub Institute for Alzheimer’s and Aging Research provide the supportive framework and collaborative opportunities to make this possible.