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: 8054782
• 负责人: Vivek Unni
• 金额: $ 1.92万
• 依托单位: MASSACHUSETTS GENERAL HOSPITAL
• 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 2011-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8054782
• 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; 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（由申请人提供）：本项目的主要目标是将复杂的体内成像、生物化学和神经病理学技术应用于帕金森病小鼠模型，以检验我们下面列出的中心假设。候选人的长期目标是管理一个独立的研究小组，专注于了解帕金森病中神经退行性疾病的发生方式，并作为运动障碍专家进行医学实践。拟议的工作将在马萨诸塞州总医院（MGH）的神经内科进行，在布拉德利海曼博士的实验室进行，他是神经变性研究的公认领导者，在指导年轻的医生科学家方面有着出色的记录。蛋白质可以以多种聚集状态存在于细胞中，其中一些被认为产生毒性作用，引起许多神经退行性疾病。我们的中心假设是，活脑中的神经元使用不同的特定机制从细胞中清除不同大小的蛋白质聚集体。通过将体内多光子成像、生物化学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质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个特定假设：假设1）自噬途径降解较大的1-突触核蛋白聚合物。假设2）蛋白酶体途径降解1-突触核蛋白的较小聚集体种类。假设3）受损的蛋白质清除导致突触前1-突触核蛋白聚集和突触变性。这些研究将有助于表征1-突触核蛋白的水平是如何被神经元调节的;更好地理解这种调节可能会导致治疗帕金森病的新的治疗策略。除了为以疾病为重点的基础研究提供时间外，该提案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内容。这些重要的组成部分包括由该领域的领导者进行结构化指导;在神经退行性疾病，统计学，生物成像和负责任的研究行为领域的具体课程;以及在MGH运动障碍诊所评估和治疗帕金森病和相关疾病的时间。 公共卫生关系：这项研究的目的是更好地了解导致帕金森病和相关疾病脑细胞死亡的机制。希望这项工作将揭示一些参与神经退行性疾病的特定细胞通路，以便它们可以成为治疗这些疾病的新药开发的靶点。