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

描述（由申请人提供）：该项目的主要目标是将复杂的体内成像，生化和神经病理学技术应用于帕金森病小鼠模型，以验证我们的中心假设如下。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的神经变性是如何发生的，并作为一名运动障碍专家进行医学实践。这项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，他是神经退行性疾病研究领域的知名领导者，在指导年轻的内科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，其中一些被认为会产生引起许多神经退行性疾病的毒性作用。我们的中心假设是，活体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，候选人将验证与1-突触核蛋白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-突触核蛋白聚集物。假设2)蛋白酶体途径降解较小的1-突触核蛋白聚集体。假设3)蛋白清除受损导致突触前1-突触核蛋白聚集和突触变性。这些研究将有助于描述神经元如何调节1-突触核蛋白的水平；更好地了解这种调节可能会导致治疗帕金森病的新治疗策略。除了为基础疾病研究提供时间外，该提案还包括旨在帮助候选人过渡到独立的医生-科学家职业的具体组成部分。这些重要的组成部分包括由该领域的领导者提供结构化的指导；在神经退行性疾病、统计学、生物成像和负责任的研究行为等领域的特定课程；以及在MGH运动障碍诊所评估和治疗帕金森病及相关疾病患者的时间。

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.