PD iPS Cell Line Research Consortium

PD iPS 细胞系研究联盟

基本信息

批准号：
7890698
负责人：
OLE ISACSON
金额：
$ 188.55万
依托单位：
MCLEAN HOSPITAL
依托单位国家：
美国
项目类别：
财政年份：
2009
资助国家：
美国
起止时间：
2009-09-30 至 2011-08-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/7890698
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

项目摘要

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。该联盟由多个拥有 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（参见领导计划）的总体目标是将快速扩展的 iPS 干细胞领域组织成有用的科学应用和评估，以用于临床导向的 PD 研究。组织结构包括一个用于生成 iPS 细胞系并将其分发给研究团队的集中站点，以及一个安全网站 (www.PDiPS.org)。该中心设施（核心 A）位于麦克莱恩/哈佛大学，由 Drs. 领导。 Isacson, Feng（纽约州立大学）和麻省理工学院的 Jaenisch。该核心功能还与用于患者材料和分析的临床核心（核心 B，与项目 1 - Wszolek 博士密切合作）相关联，由哥伦比亚大学的 Karen Marder 博士领导。这些类型的活动均被记录并与数据库（pd.doc 和 dbGaP）协调，了解已知的 PD 突变和临床病史，并在 Coriell 细胞存储库中建立 PD 患者成纤维细胞和血细胞库，该存储库还存放 Core 生成的 PD iPS 细胞系A. 核心A和B完成干细胞iPS细胞系的基本表征后，将这些细胞分发给优秀的研究团队。项目 1：研究团队 1 涉及遗传和基因组分析团队，该团队还提供对新突变的深入了解，无论是在家族还是遗传关联水平上作为危险因素。该团队由担任临床主任的 Zbigniew Wszolek 和负责基因研究的 Matt Farrer（饰演 Pis）领导。他们最近的分析和基因技术将有利于后续工作。项目 2 对各种细胞系进行了分子表征。该团队由 Ted Dawson 博士领导，他将与其合作者合作，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 博士进行合作，他们已经开始建立这些细胞系以进行分子表征。在项目 3 中，由 Drs. 领导的宾夕法尼亚大学研究小组Lee和Trojanowski将研究PD患者iPS细胞的PD蛋白加工、降解和自噬分析。他们在该领域的杰出专业知识将允许对与此类细胞生物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，也是对 PD iPS 细胞衍生的 DA 神经元进行长期评估的关键体内生物测定。该项目团队由博士领导。 Isacson 和 Surmeier 将合作进行体外和体内检测，以检测 PD iPS 衍生细胞的任何改变的电生理和神经毒性反应；提供有关神经元/神经生长、脆弱性和钙缓冲能力的疾病神经生物学信息。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 分子机制和线粒体病理学。总体而言，该 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 资助将使一个联盟能够快速提供与 PD 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，并作为有用的试剂提供给当前和未来的 PD 研究人员。公共健康相关性：我们使用帕金森病患者皮肤产生的干细胞来产生特定的纯化神经元群体，保留了该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受到帕金森病样变性的影响。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。