Protein Aggregation & Modification in Neurodegeneration

蛋白质聚集

• 批准号: 7037201
• 负责人: Matthew J Lavoie
• 金额: $ 12.97万
• 依托单位: BRIGHAM AND WOMEN'S HOSPITAL
• 依托单位国家: 美国
• 财政年份: 2006
• 资助国家: 美国
• 起止时间: 2006-03-15 至 2011-02-28
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7037201
• 关键词: Parkinson' s disease; alpha synuclein; apoptosis; cell line; chemical aggregate; cytochrome c; dopamine; human tissue; mitochondria; neural degeneration; oxidative phosphorylation; oxidative stress; parkin gene /protein; posttranslational modifications; quinones

DESCRIPTION (provided by applicant): I have spent all of my professional training involved in the study of neurodegenerative disease with an early background in Parkinson's disease, and a purposefully sought postdoctoral position in the laboratory of Dr. Dennis Selkoe at the Center for Neurologic Disease (CND). I have begun an independent line of research clearly distinct from that of my mentor, and seek NIH support to further these studies under the continued guidance of Dr. Selkoe. I have chosen Dr. Selkoe as my mentor because: a) he is a recognized leader in the field of neurodegenerative disease-related cell biology with a remarkable history of training successful, independent researchers early in their careers, b) the Selkoe laboratory continues to provide a stimulating environment focused on issues of protein aggregation, protein-protein interactions in neurodegenerative disease and cell signaling and c) the support of the CND, and of Dr. Selkoe in particular, demonstrate a strong commitment to my continued development as an independent investigator. The CND is an ideal environment to conduct basic research in neurodegeneration, as it is the sole focus of its 14 principal investigators. Furthermore, there is liberal access to the vast resources of the Harvard Center for Neurodegenerative Disease and Repair, as well as collaborative and training opportunities throughout Harvard Medical School. My preliminary data demonstrate that the neurotransmitter dopamine (DA) itself adversely affects Parkin function, causing aggregation and oligomerization of the Parkin protein and inactivation of its E3 ligase activity. These data suggest that DA may contribute to a partial Parkin loss of function in idiopathic PD. The focus of the first 2 Aims of this proposal is to characterize the selective vulnerability of Parkin to modification by DA and determine whether this post-translational modification can be found in human brain. The training goals of this K01 application are to expand my expertise to include protein chemistry and mass spectrometric analyses, relevant to the growing interest in post-translational modification (i.e., Parkin) and cleavage (i.e., a-synuclein) of proteins in neurological disease. Additionally, I propose to gain expertise in the study of appptosis and the role mitochondria play in cell death under the tutelage of Dr. Stanley Korsmeyer. This collaboration is directly relevant to the model of dopamine-induced Parkin deficiency outlined herein, and would provide a world-class training experience in the execution of Aim 3: to determine whether Parkin deficiency promotes mitochondria-induced apoptosis.

简介(申请人提供)：我接受的所有专业培训都涉及神经退行性疾病的研究，具有帕金森氏病的早期背景，并有意在神经疾病中心(CND)的Dennis Selkoe博士的实验室寻求博士后职位。我已经开始了一项独立的研究，与我的导师的研究明显不同，并寻求NIH的支持，以在塞尔科博士的持续指导下进一步推进这些研究。我选择Selkoe博士作为我的导师是因为：a)他是神经退行性疾病相关细胞生物学领域公认的领导者，在职业生涯早期培训成功的独立研究人员方面有着非凡的历史；b)Selkoe实验室继续提供专注于蛋白质聚集、神经退行性疾病中的蛋白质-蛋白质相互作用和细胞信号转导问题的刺激环境；c)CND，尤其是Selkoe博士的支持表明，我作为一名独立研究员，对持续发展有着坚定的承诺。CND是进行神经变性基础研究的理想环境，因为它是其14名主要研究人员的唯一重点。此外，哈佛大学神经退行性疾病和修复中心的大量资源以及整个哈佛医学院的合作和培训机会都是可以自由使用的。 我的初步数据显示，神经递质多巴胺(DA)本身对 Parkin功能，导致Parkin蛋白的聚集和寡聚及其失活 E3连接酶活性。这些数据表明，DA可能是导致帕金氏病部分功能丧失的原因之一。 特发性帕金森病。这项提案的前两个目标的重点是描述选择性的 Parkin对DA修改的漏洞，并确定此翻译后 在人脑中可以发现基因的修饰。此K01应用程序的培训目标是扩展 我的专业知识包括蛋白质化学和质谱分析，与不断增长的 对蛋白质的翻译后修饰(即Parkin)和切割(即a-突触核蛋白)感兴趣 神经系统疾病。此外，我还建议在细胞凋亡及其作用的研究方面获得专业知识。 在斯坦利·科斯迈尔博士的指导下，线粒体在细胞死亡中发挥了作用。此次合作是 与本文概述的多巴胺诱导的帕金氏缺乏症模型直接相关，并将 在执行目标3：确定是否停车方面提供世界级培训体验 缺乏促进线粒体诱导的细胞凋亡。