Protein Aggregation & Modification in Neurodegeneration

描述（由申请人提供）：我的所有专业训练都涉及神经退行性疾病的研究，早期有帕金森病的背景，并有目的地在神经疾病中心（CND）的Dennis Selkoe博士实验室寻求博士后职位。我已经开始了一条与我的导师截然不同的独立研究路线，并在Selkoe博士的继续指导下寻求NIH的支持来进一步研究。我选择塞尔科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，在职业生涯早期培养成功、独立的研究人员方面有着非凡的历史；b) Selkoe实验室继续提供一个刺激的环境，专注于蛋白质聚集、神经退行性疾病和细胞信号中的蛋白质-蛋白质相互作用问题；c) CND的支持，尤其是Selkoe博士。表现出对我作为独立调查员继续发展的坚定承诺。CND是进行神经退行性疾病基础研究的理想环境，因为它是其14位主要研究人员的唯一焦点。此外，还可以自由使用哈佛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。

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.