The regulation of alpha-synuclein and neurodegeneration in Parkinson's Disease

帕金森病中α-突触核蛋白和神经变性的调节

• 批准号: 8267045
• 负责人: Vivek Unni
• 金额: $ 18.23万
• 依托单位: OREGON HEALTH & SCIENCE UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2010
• 资助国家: 美国
• 起止时间: 2010-08-01 至 2015-05-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8267045
• 关键词: Animals; Autophagocytosis; Biochemical; Biological; Biological Assay; Brain; Brain Diseases; Brain region; Cell Size; Cells; Cessation of life; Clinic; Detergents; Disease; Focus Groups; General Hospitals; Goals; Green Fluorescent Proteins; Human; Image; Immunohistochemistry; Investigation; Laboratories; Lead; Lewy Body Disease; Life; Link; Massachusetts; Measures; Medicine; Mentors; Molecular Sieve Chromatography; Movement Disorders; Mus; Names; Nerve Degeneration; Neurodegenerative Disorders; Neurologic; Neurology; Neurons; Parkinson Disease; Parkinson' s Dementia; Pathway interactions; Patients; Pb clearance; Pharmacology; Physicians; Play; Presynaptic Terminals; Proteins; Reagent; Regulation; Research; Research Proposals; Role; Running; Scientist; Solubility; Specialist; Structure; Synapses; Techniques; Testing; Time; Toxic effect; Wild Type Mouse; Work; alpha synuclein; brain cell; career; density; drug development; gel electrophoresis; in vivo; monomer; mouse model; multicatalytic endopeptidase complex; novel therapeutics; presynaptic; protein aggregate; protein aggregation; protein metabolism; public health relevance; research study; responsible research conduct; statistics; synuclein; synucleinopathy; tomography

DESCRIPTION (provided by applicant): The primary goal of this project is to apply sophisticated in vivo imaging, biochemical, and neuropathological techniques to mouse models of Parkinson's Disease in order to test our central hypothesis listed below. The long-term goal of the candidate is to run an independent research group focused on understanding how neurodegeneration occurs in Parkinson's disease and to practice medicine as a movement disorders specialist. The proposed work will be carried out in the Neurology Department at Massachusetts General Hospital (MGH), in the laboratory of Dr. Bradley Hyman, an established leader in neurodegeneration research with an excellent track record of mentoring young physician-scientists. Proteins can exist in the cell in a number of aggregated states, some of which are thought to produce the toxic effects that give rise to many neurodegenerative diseases. Our central hypothesis is that neurons in the living brain use different specific mechanisms for clearing protein aggregates of varying sizes from the cell. By combining in vivo multiphoton imaging, biochemical, and neuropathological techniques with pharmacological approaches, the candidate will test 3 specific hypotheses related to how the abnormal metabolism of the protein 1-synuclein may lead to Parkinson's Disease and related disorders: Hypothesis 1) An autophagic pathway degrades larger aggregate species of 1-synuclein. Hypothesis 2) The proteasome pathway degrades smaller aggregate species of 1-synuclein. Hypothesis 3) Impaired protein clearance leads to presynaptic 1-synuclein aggregation and synaptic degeneration. These investigations will help to characterize how levels of 1-synuclein protein are regulated by neurons; a better understanding of this regulation could to lead to new therapeutic strategies to treat Parkinson's Disease. In addition to providing time for basic disease-focused research, this proposal includes specific components directed towards helping the candidate transition into an independent physician-scientist career. These important components include structured mentoring by a leader in the field; specific coursework in the fields of neurodegeneration, statistics, biological imaging, and the responsible conduct of research; and time evaluating and treating patients with Parkinson's Disease and related disorders in the MGH Movement Disorders clinic. PUBLIC HEALTH RELEVANCE: The goal of the proposed research is to better understand what mechanisms lead to the death of brain cells in Parkinson's Disease and related disorders. It is hoped that this work will reveal some of the specific cellular pathways involved in neurodegeneration so that they can become targets for new drug development to treat these diseases.

描述(申请人提供)：该项目的主要目标是将复杂的活体成像、生化和神经病理学技术应用于帕金森氏病的小鼠模型，以检验我们下面列出的中心假设。这位候选人的长期目标是管理一个独立的研究小组，专注于了解帕金森氏症神经变性是如何发生的，并以运动障碍专家的身份行医。这项拟议的工作将在马萨诸塞州总医院(MGH)的神经科进行，在布拉德利·海曼博士的实验室里进行。海曼博士是神经退行性疾病研究的知名领导者，在指导年轻内科科学家方面有着良好的记录。蛋白质可以在细胞中以多种聚集状态存在，其中一些被认为会产生毒性效应，导致许多神经退行性疾病。我们的中心假设是，活着的大脑中的神经元使用不同的特定机制来清除细胞中不同大小的蛋白质聚集体。通过将体内多光子成像、生化和神经病理学技术与药理学方法相结合，候选人将测试与蛋白1-突触核蛋白的异常代谢如何导致帕金森病和相关疾病相关的3个具体假说：假设1)自噬途径降解较大的1-突触核蛋白聚集体物种。假设2)蛋白酶体途径降解1-突触核蛋白的较小聚集物种。假设3)蛋白质清除受损导致突触前1-突触核蛋白聚集和突触变性。这些研究将有助于表征神经元是如何调节1-突触核蛋白水平的；更好地理解这种调节可能会导致治疗帕金森氏症的新的治疗策略。除了为以疾病为重点的基础研究提供时间外，这项建议还包括旨在帮助候选人过渡到独立的医生-科学家职业生涯的具体组成部分。这些重要组成部分包括该领域领导者的结构化指导；神经退行性变、统计学、生物成像和负责任的研究领域的具体课程工作；以及在MGH运动障碍诊所评估和治疗帕金森氏病和相关疾病患者的时间。 公共卫生相关性：这项拟议研究的目标是更好地了解帕金森氏病和相关疾病中导致脑细胞死亡的机制。人们希望这项工作将揭示一些涉及神经退行性变的特定细胞通路，以便它们能够成为治疗这些疾病的新药开发的靶点。