PD iPS Cell Line Research Consortium

PD iPS 细胞系研究联盟

• 批准号: 8145814
• 负责人: OLE ISACSON
• 金额: $ 7.9万
• 依托单位: MCLEAN HOSPITAL
• 依托单位国家: 美国
• 财政年份: 2009
• 资助国家: 美国
• 起止时间: 2009-09-30 至 2012-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8145814
• 关键词: Affect; Age; Arts; Autophagocytosis; Basic Science; Bioenergetics; Biological Assay; Biological Process; Biopsy; Blood; Blood Cells; Buffers; Calcium; Cell Line; Cell Transplants; Cell physiology; Cells; Clinical; Clinical Data; Collaborations; Communities; Complement; Complex; Core Facility; Corpus striatum structure; DNA Methylation; Data; Databases; Deposition; Diagnostic; Disease; Dopaminergic Cell; Environment; Evaluation; Exhibits; Fibroblasts; Future; Gel; Gender; Gene Expression; Gene Expression Profile; Gene Expression Profiling; Gene Mutation; Genes; Genetic; Genetic Risk; Genetic screening method; Genome; Genomics; Goals; Grant; Growth; Head; Human; In Vitro; Individual; Investigation; LRRK2 gene; Leadership; Link; Messenger RNA; MicroRNAs; Mitochondria; Molecular; Molecular Profiling; Motor; Mutation; National Institute of Neurological Disorders and Stroke; Nerve Degeneration; Neurobiology; Neurons; Oxidative Stress; Parkinson Disease; Pathology; Pathway interactions; Patients; Pattern; Phenotype; Physiological; Population; Predisposition; Process; Proteins; Proteomics; RNA; Reagent; Recording of previous events; Recruitment Activity; Reporting; Research; Research Personnel; Resources; Risk Factors; Secure; Site; Skin; Somatic Cell; Stem cells; Toxin; Transplantation; Universities; Work; cell bank; cohort; database of Genotypes and Phenotypes; disorder control; dopaminergic neuron; drug discovery; genetic association; genetic technology; in vivo; in vivo Bioassay; induced pluripotent stem cell; insight; mouse model; multidisciplinary; neurotoxic; novel strategies; organizational structure; protein expression; public health relevance; repository; response; stressor; tool; web site

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.

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、表征和研究用于帕金森病（PD）的iPS细胞系。该联盟由几个顶尖的研究团队组成，拥有PD的临床和基础科学专业知识。这个由多个PI组成的联盟的总体目标（见领导计划）是将快速扩展的iPS干细胞领域组织成有用的科学应用和临床导向PD研究的评估。组织结构包括一个集中的网站，以产生iPS细胞系，并将其分发给研究团队，以及一个安全的网站（www.PDiPS.org）。这个中心设施（核心A）可在姆克林/哈佛，并由Isacson博士，冯（纽约州立大学）和Jaenisch在麻省理工学院领导。该核心功能还与临床核心（核心B，与项目1 - Dr Wszolek密切合作）相关联，用于患者材料和分析，由哥伦比亚大学的Karen Marder博士领导。记录这些类型的活动，并与已知PD突变和临床病史的数据库（pd.doc和dbGaP）进行协调，在Coriell细胞库中建立PD患者成纤维细胞和血细胞库，该库还存放由Core A生成的PD iPS细胞系。通过核心A和B完成干细胞iPS细胞系的基本表征，将其分发给优秀的研究团队。项目一：研究团队1包括遗传和基因组分析团队，该团队还提供了对新突变的深入了解，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和遗传研究的Matt Farrer（作为Pis）领导。他们最近的分析和遗传技术将有利于继续开展工作。在项目2中，对各种细胞系进行了分子表征。该团队由Ted Dawson博士领导，他将与他的合作者合作，对相关PD患者材料进行iPS线分析。Dawson博士目前还通过项目1与Wszolek博士合作，他们已经开始建立这些细胞系进行分子表征。在项目3a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与这些细胞生物学过程相关的变化的最先进的分析。项目4将是一项重要的体外生理学和毒理学分析，以及长期评价PD iPS细胞衍生DA神经元的关键体内生物测定。该项目团队由Isacson和Surmeier博士领导，他们将合作进行PD iPS衍生细胞的任何改变的电生理和神经毒性反应的体外和体内试验;提供神经元/神经炎生长，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神经元中线粒体的高度相关的PD分子机制和病理学。总的来说，这个PD iPS联盟将拥有卓越的研究能力，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提供与PD相关的iPS细胞系的国家资源，由组装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PD研究人员的大社区。 公共卫生相关性：我们使用从帕金森病患者皮肤中产生的干细胞来产生特定的纯化神经元群体，这些神经元保留了疾病的真实遗传风险。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病样变性。我们的数据旨在将这些神经元建立为理解复杂疾病过程的强大新方法和未来药物发现的工具。