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、表征和研究帕金森氏病(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PI组成的联盟(见领导计划)的总体目标是将迅速扩大的iPS干细胞领域组织成有用的科学应用和评估，用于临床导向的帕金森病研究。该组织结构包括一个中央网站，用于生成iPS细胞系，以便将这些细胞系分发给研究团队，以及一个安全网站(www.PDiPS.org)。这个中心设施(核心A)位于麦克莱恩/哈佛大学，由麻省理工学院的伊萨克森、冯博士(纽约州立大学)和雅尼施博士领导。这一核心职能还与临床核心(核心B，与项目1-Wszolek博士密切合作)联系在一起，用于患者材料和分析，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突变和临床病史的数据库(PDF和DBGaP)相协调，PD患者的成纤维细胞和血细胞库在Coriell细胞库建立，该库还存储由Core A产生的PD iPS细胞系与由Core A和B完成的干细胞iPS细胞系的基本特征，这些被分发给优秀的研究团队。项目1：研究团队1包括一个遗传和基因组分析团队，该团队还提供了对新突变的洞察，包括在家族和基因关联层面上的风险因素。该团队由临床主任Zbigniew Wszolek和遗传学研究的Matt Farrer(Pis)领导。他们最近的分析和基因技术将有助于继续工作。在项目2中，有各种细胞系的分子特征。该团队由Ted Dawson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系列分析。道森博士目前还通过项目1与Wszolek博士进行了合作，他们已经在着手建立这些细胞系，用于分子鉴定。在项目3中，由Lee博士和Trojanowski博士领导的宾夕法尼亚大学研究小组将对PD患者iPS细胞的PD蛋白处理、降解和自噬分析进行调查。他们在这一领域的杰出专业知识将使我们能够对与这种细胞生物学过程相关的变化进行最先进的分析。项目4将是一项重要的体外生理和毒理学分析，也是长期评估PD iPS细胞来源的DA神经元的关键在体生物测定。该项目团队由Isacson博士和Surmeier博士领导，他们将通过合作对PD iPS来源细胞的任何改变的电生理和神经毒性反应进行体外和体内测试；提供关于神经元/神经元生长、脆弱性和钙缓冲能力的疾病信息的神经生物学。最后，由Serge Przedborski博士领导的项目5将研究分化的PD iPS神经元中高度相关的PD分子机制和线粒体的病理。总体而言，这个PD iPS联盟将拥有非凡的研究能力，目前已准备好通过各个研究团队的独立优势和专业知识进行部署。GO赠款将使一个财团能够迅速为与帕金森病相关的iPS细胞系提供全国资源，由聚集的合作者以有意义的方式进行表征，并作为有用的试剂提供给现在和未来的帕金森病研究人员的大社区。 公共卫生相关性：我们使用从帕金森氏病患者皮肤中产生的干细胞来产生特定数量的纯化神经元，这些神经元保留了该疾病真实的遗传风险。我们将确定这些神经元是否比健康人皮肤产生的神经元更容易发生帕金森氏病样变性。我们的数据旨在将这些神经元确立为了解复杂疾病过程的一种强有力的新方法，并成为未来药物发现的工具。

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.