Generation and Characterization of Amyotrophic Lateral Sclerosis

肌萎缩侧索硬化症的产生和特征

• 批准号: 8288399
• 负责人: KEVIN C EGGAN
• 金额: $ 84.96万
• 依托单位: JOHNS HOPKINS UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2012
• 资助国家: 美国
• 起止时间: 2012-07-01 至 2014-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8288399
• 关键词: Amyotrophic Lateral Sclerosis; Astrocytes; Biological Assay; Biology; Cell Communication; Cell Line; Cells; Characteristics; Collaborations; Collection; Complement; Development; Disease; Functional disorder; Future; Generations; Genetic; Human; Human Cell Line; Lead; Motor Neurons; Mutation; Pathogenesis; Pathway Analysis; Patients; Principal Investigator; Reporter; Specificity; System; Therapeutic; Work; Zinc Fingers; base; cell type; disease phenotype; drug discovery; genetic analysis; human embryonic stem cell; induced pluripotent stem cell; insight; meetings; novel; novel therapeutics; pluripotency; relating to nervous system; tool

DESCRIPTION (provided by applicant): Induced Pluripotent Cells (IPS) from ALS patients could provide an exceptional tool by which we can disease pathophysiology and druggable targets. Many recent insights into the pathophysiology of ALS come from the study of familial forms of this disease. The ability to actually have human cell lines representing the natural disease in the most relevant cell types- motor neurons and astrocytes- provides unprecedented tools to 1) study cell interactions responsible for disease pathophysiology and 2) provide critical tools for drug discovery and genetic pathway analysis. We have generated iPS cell lines, under identical conditions, from various familial ALS (fALS) mutations and sporadic ALS (sALS) patients to determine how representative they are for cell type specificity and functional biology. The first set of cells now generated, are ready for use in disease phenotyping paradigms. The overall proposal will involve four principal investigators, working in tight collaboration, to generate and evaluate fALS and sALS cell lines and to use them to develop cell specific phenotypic assays. Project 1, lead by Dr. Eggan will generate new critical IPS line- isogenic liens from selected fALS mutations as well as non-integrating IPS lines- to complement our retroviral based IPS collection. In addition Project 1 will fully evaluate the pluripotency of the lines using a novel genetic scorecard system. iPS cell lines with neural/glial characteristics will be sent to the Project 2 Lab- Motor neuron biology, lead by Chris Henderson and to Project 3 lab. Astrocytes- lead by Jeffrey Rothstein. These two projects/labs will determine which ofthe fALS IPS cell lines have the appropriate characteristics of motor neurons and astroglia, thru sequential analyses. In addition, both groups will generate Zinc-finger based cell specific reporter cell lines for future use in drug discovery assays. Cell lines that meet final criteria (a compared to human ES cell and prior work on human astroglia) will undergo genetic analysis in the Project 4 lab, lead by Tom Maniatis. Finally, to develop useful tools for therapeutics and pathogenesis, Cores 1 and 2 will generate motor neuron and astroglial disease phenotyping assays. PUBLIC HEALTH RELEVANCE: Understanding the pathophysiology and development of new therapeutics for ALS has been an enormous challenge. The ability to actually have human cell lines- representing the natural disease in the most relevant cell types- motor neurons and astrocytes- will provide unprecedented tools to 1) study interactions responsible for disease pathophysiology and 2) provide critical tools for drug discovery.

描述（由申请人提供）：来自ALS患者的诱导多能细胞（IPS）可以提供一个特殊的工具，我们可以通过它来研究疾病病理生理和药物靶点。最近对ALS病理生理学的许多见解来自对这种疾病的家族形式的研究。人类细胞系在最相关的细胞类型（运动神经元和星形胶质细胞）中代表自然疾病的能力，为1)研究导致疾病病理生理学的细胞相互作用和2)提供了前所未有的工具