Protein Aggregation and Modification in Neurodegeneration

我所有的专业训练都是在神经退行性疾病的研究中度过的， 帕金森病的早期背景，以及有目的地寻求博士后职位， 神经疾病中心（CND）的Dennis Selkoe博士实验室。我已经开始了 独立的研究路线明显不同于我的导师，并寻求NIH的支持，以进一步 这些研究在Selkoe博士的持续指导下进行。我选择塞尔科博士作为我的导师 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 具有在职业生涯早期培养成功的独立研究人员的卓越历史，B） 塞尔科实验室继续提供一个刺激性的环境，重点是蛋白质问题 聚集，神经变性疾病和细胞信号传导中的蛋白质-蛋白质相互作用，和c） CND的支持，特别是Selkoe博士的支持，表明了对我的坚定承诺。 作为一名独立调查员继续发展。CND是一个理想的环境， 进行神经变性的基础研究，因为这是其14名主要研究人员的唯一重点。 此外，人们可以自由地使用哈佛中心的大量资源， 神经退行性疾病和修复，以及合作和培训机会 整个哈佛医学院。 我的初步数据表明，神经递质多巴胺（DA）本身对 帕金功能，导致帕金蛋白的聚集和寡聚化以及其失活。 E3连接酶活性。这些数据表明，DA可能有助于部分帕金功能丧失， 特发性帕金森病本提案的前两个目标的重点是描述选择性 Parkin对DA修饰的脆弱性，并确定这种翻译后 在人脑中也能发现这种变化。此K 01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，相关的增长， 对翻译后修饰感兴趣（即，Parkin）和乳沟（即，a-突触核蛋白）的蛋白质， 神经系统疾病此外，我建议获得专业知识，在研究下垂和作用， 在Stanley Korsmeyer博士的指导下，线粒体在细胞死亡中发挥作用。开展此种合作 与本文概述的多巴胺诱导的帕金缺乏症模型直接相关， 提供世界一流的培训经验，在执行目标3：以确定是否帕金 缺乏促进了BRA诱导的细胞凋亡。

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.