PD iPS Cell Line Research Consortium

描述（由申请人提供）：我们已经为NINDS研究组织/联盟制定了一项计划，以开发，表征和研究帕金森病（PD）的iPS细胞系。该联盟由几个具有PD临床和基础科学专业知识的顶级研究团队组成。这个由多个Pis组成的联盟的总体目标是将快速扩展的iPS干细胞领域组织为临床导向的PD研究的有用科学应用和评估。组织结构包括：制作iPS细胞系并分发给各研究组的集中网站和安全网站（www.PDiPS.org）。这个中心设施（核心A）在麦克莱恩/哈佛大学可用，由博士领导。Isacson, Feng（纽约州立大学）和麻省理工学院的Jaenisch。该核心功能还与临床核心（核心B，与项目1 - Wszolek博士密切合作）相关联，用于患者资料和分析，由哥伦比亚大学的Karen Marder博士领导。这些类型的活动被记录下来，并与已知PD突变和临床史的数据库（PD .doc和dbGaP）进行协调，PD患者成纤维细胞和血细胞库在科里ell细胞库中储存，其中还存放了由Core A生成的PD iPS细胞系。Core A和B完成了干细胞iPS细胞系的基本表征，这些被分发给优秀的研究团队。项目1：研究小组1包括一个遗传和基因组分析小组，该小组还提供了对新突变的见解，无论是在家族和遗传关联水平上，都是风险因素。该团队由临床主任Zbigniew Wszolek和基因研究的Matt Farrer领导（Pis）。他们最近的分析和基因技术将有利于继续工作。在项目2中有各种细胞系的分子表征。该团队由泰德·道森博士领导，他将与他的合作者一起从PD患者的相关材料中进行iPS系分析。道森博士目前也与Wszolek博士通过项目1进行合作，他们已经开始建立这些细胞系进行分子表征。在项目3中，宾夕法尼亚大学的一个研究小组由博士领导。Lee和Trojanowski将对PD患者iPS细胞的PD蛋白加工、降解和自噬分析进行研究。他们在这一领域的杰出专业知识将允许对与此类细胞生物学过程相关的变化进行最先进的分析。项目4将是一个重要的体外生理和毒理学分析，以及重要的体内生物分析，以长期评估PD iPS细胞来源的DA神经元。这个项目组由dr。Isacson和Surmeier将合作对PD诱导多能干细胞衍生细胞的电生理和神经毒性反应进行体内和体外检测；为神经元/神经炎生长、易损性和钙缓冲能力提供疾病的神经生物学信息。最后，由Serge Przedborski博士领导的项目5将研究高度相关的PD分子机制和分化的PD iPS神经元中线粒体的病理。总的来说，这个PD知识产权联盟将拥有卓越的研究能力，目前已准备好利用各个研究团队的独立优势和专业知识进行部署。GO拨款将使一个联盟能够迅速提供与帕金森病相关的iPS细胞系的国家资源，由聚集的合作者以有意义的方式进行表征，并为现在和未来的帕金森病研究人员提供有用的试剂。

DESCRIPTION (provided by applicant): We have developed a plan for a NINDS research organization/consortium to develop, characterize and study iPS cell lines for Parkinson's disease (PD). The consortium is organized with several top research teams with both clinical and basic science expertise for PD. The overall goal of this consortium of multiple- Pis (see leadership plan) is to organize the rapidly expanding iPS stem cell field into useful scientific applications and evaluations for clinically oriented PD research. The organizational structure includes a centralized site to generate the iPS cell lines to distribute these to the research teams, and a secure website (www.PDiPS.org). This central facility (Core A) is available at McLean/Harvard and is led by Drs. Isacson, Feng (SUNY) and Jaenisch at MIT. This Core function is also linked with a clinical core (Core B, in close collaboration with Proj 1 - Dr Wszolek) for patient material and analysis, headed by Dr Karen Marder at Columbia University. These types of activities are recorded and coordinated with databases (pd.doc and dbGaP) for known PD mutations and clinical histories, with PD patient fibroblast and blood cell banking made at Coriell cell repository, which also deposits the PD iPS cell lines generated by Core A. With the stem cell iPS cell lines basic characterization fulfilled by Core A and B, these are distributed to the outstanding investigative teams. Project 1: Research team 1 involves both a genetic and genomic analysis team, which also provides insight into new mutations, both at the familial and genetic association level as risk factors. This team is led by Zbigniew Wszolek as a clinical director and Matt Farrer for genetic studies (as Pis). Their recent analysis and genetic technology will benefit the continued work. In Project 2 there is a molecular characterization of the various cell lines. This team is headed by Dr. Ted Dawson, who will be working with his collaborators to have iPS line analyses from relevant PD patient material. Dr. Dawson also has a current collaboration through Project 1 with Dr. Wszolek, and they are already moving towards setting up these cell lines for molecular characterization. In Project 3 a U. Penn research team led by Drs. Lee and Trojanowski will carry out investigation into PD protein processing, degradation and autophagy analysis of PD patients' iPS cells. Their outstanding expertise in this field will allow a state of the art analysis of changes relevant to such cell biological processes. Project 4 will be an essential in vitro physiological and toxicological analysis, and critical in vivo bioassays for long-term evaluation of PD iPS cell derived DA neurons. This project team is headed by Drs. Isacson and Surmeier, who by collaboration will perform both in vitro and in vivo assays for any altered electrophysiologic and neurotoxic response of the PD iPS derived cells; providing neurobiology of disease information for neuronal/neuritic growth, vulnerability and calcium buffering capacities. Finally, Project 5, headed by Dr Serge Przedborski, will examine the highly relevant PD molecular mechanisms and pathology of mitochondria in differentiated PD iPS neurons. Overall, this PD iPS consortium will have an exceptional research capacity, which is currently ready to deploy by the independent strengths and expertise of the individual research teams. The GO grant will enable a consortium that quickly can provide a national resource for iPS cell lines relevant to PD, to be characterized in a meaningful way by the assembled collaborators, and made available as useful reagents to the large community of present and future PD researchers. PUBLIC HEALTH RELEVANCE: We use stem cells generated from Parkinson's disease patients' skin to produce a specific population of purified neurons that retain the authentic genetic risks for the disease. We will determine if these neurons are more susceptible to Parkinson's disease-like degeneration than neurons generated from healthy people's skin. Our data will aim to establish these neurons as a powerful new approach to understanding the complex disease process and a future tool for drug discovery.