Do Ariadne and Parkin Share Redundant Function

首席调查员/ pirgerca （tLomar）施瓦兹，LM。描述：说明申请的广泛、长期目标和具体目的，并参考项目与健康的关系。简要描述为实现这些目标的研究设计和方法。避免总结过去的成就和使用第一人称。当与应用程序分离时，此描述旨在作为对所建议工作的简洁而准确的描述。如果申请得到资助，这种帕金森病（PD）是美国第二常见的神经退行性疾病。最近，一些常染色体隐性青少年帕金森病（AR-JP）家族被证明携带一种称为Parkin的基因突变，这是一种泛素E3连接酶。NINDS最近确定了Parkin及其相关蛋白作为深入研究的靶点（RFA NS- 01-005）。在这篇文章中，我们将重点放在阿里阿德涅身上，这是已知与帕金最接近的结构同源物。阿里阿德涅蛋白是一种特征较差的蛋白，其整体结构组织与帕金蛋白相似。阿里阿德涅和帕金都与相同的泛素E2酶结合，在果蝇中，阿里阿德涅的丧失导致生存能力降低和静止震颤。在初步研究中，我们已经证明阿里阿德涅和帕金具有显著的结构和时间特性。在本提案中，我们将使用生化，分子，细胞和遗传学方法来验证阿里阿德涅和帕金是结构和功能同源的假设：1)结构和功能同源；2)参与路易体形成；3)保护体内和体外细胞免受有害刺激。这项工作可能使我们能够：1)解释为什么帕金全局功能丧失突变的表型效应主要局限于多巴胺能神经元；2)验证路易体样细胞质包涵体反映细胞的适应性反应；和3提供了对这类蛋白质功能的深入了解，可以增强我们对细胞帕金功能的理解。描述本身将成为公开信息。因此，不要包含专有/机密信息。不要超过规定的8步。网站性能 ======================================== 节结束 ===========================================

BB PrincipInavlestigator/PDroirgerca(tLomar .ctirte,t, raiadle): Schwartz, LM. DESCRIPTION: State the application's broad, long-term objectives and specific aims, making reference to the health relatedness of the project. Describe concisely the research design and methods for achieving these goals. Avoid summaries of past accomplishments and the use of the first person. This description is meant to serve as a succinct and accurate descdpti0n of the proposed work when separated from the application. If the application is funded, this Parkinson's Disease (PD) is the second most common neurodegenerative disorder in the United States. Recently, several families with Autosomal Recessive Juvenile Parkinsonism (AR-JP) have been demonstrated to carry mutations in a gene termed Parkin, a ubiquitin E3 ligase. NINDS recently identified Parkin and related proteins as targets for intensive investigation (RFA NS- 01-005). In this proposal, we focus on Ariadne, the closest known structural homolog of Parkin. Ariadne is a poorly characterized protein with a similar overall structural organization to Parkin. Both Ariadne and Parkin bind to the same ubiquitin E2 enzymes and in Drosophila, loss of Ariadne results in reduced viability and resting tremors. In preliminary studies, we have demonstrated that Ariadne and Parkin share significant structural and ftmetional properties In this proposal, we will use biochemical, molecular, cellular and genetic methods to test the hypotheses that Ariadne and Parkin are: 1) structural and functional homologs; 2) participate in Lewy Body formation; and 3) protect cells both in vitro and in vivo from noxious stimuli. This work may allow us to: 1) explain why the phenotypic effects of global loss-of-function mutations in Parkin are largely restricted to dopaminergic neurons; 2) verify that Lewy Body-like cytoplasmic inclusions reflect an adaptive response by cells; and 3 provide insight into the functioning of this class of proteins which can enhance our understanding of Parkin function in cells. description, as is, will become public information. Therefore, do not include proprietary/confidential information. DO NOT EXCEED THE 8PACE PROVIDED. PERFORMANCE SITE ========================================Section End===========================================