Induced Pluripotent Cells for Blood Diseases

诱导多能细胞治疗血液疾病

• 批准号: 7672891
• 负责人: LEONARD Ira ZON
• 金额: $ 4.23万
• 依托单位: BOSTON CHILDREN'S HOSPITAL
• 依托单位国家: 美国
• 财政年份: 2008
• 资助国家: 美国
• 起止时间: 2008-12-01 至 2009-05-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7672891
• 关键词: Affect; Anemia; Animal Disease Models; Animal Model; Biological Assay; Biology; Blood; Bypass; Cell Line; Cells; Cellular Morphology; Chemicals; Childhood; Communities; Databases; Defect; Derivation procedure; Development; Diamond; Diamond-Blackfan anemia; Disease; Disease model; Down Syndrome; Evaluation; Fanconi' s Anemia; Fibroblasts; Foundations; Functional disorder; Genes; Genetic; Genetic Screening; Hematological Disease; Hematology; Hematopoiesis; Hematopoietic; Hereditary Disease; Human; Immunodeficient Mouse; In Vitro; Lead; Modeling; Morbidity - disease rate; Mutant Strains Mice; Pathogenesis; Pathway interactions; Patients; Phenotype; Procedures; Protocols documentation; Retroviridae; Screening procedure; Subfamily lentivirinae; Syndrome; System; Teratoma; Therapeutic; Transplantation; Work; base; body system; c-myc Genes; cell type; disease phenotype; high throughput screening; human disease; mortality; novel; novel therapeutics; pluripotency; progenitor; small hairpin RNA; small molecule; therapeutic target

DESCRIPTION (provided by applicant): The evaluation of patients with rare blood disorders has uncovered fundamental aspects of biology, pathophysiology and therapies. The affected gene for several rare genetic diseases has been recently isolated, including Diamond Blackfan anemia, Shwachman Diamond syndrome, Fanconi's anemia. The derivation of animal models for these diseases has proven difficult, as the mouse mutant phenotype does approximate the human disease in many cases. Here we propose to develop human iPS induced pluripotent cell lines from patients with genetic blood diseases (including the disorders listed above and Down's Syndrome). We plan to obtain fibroblasts from patients with the diseases, and introduce Oct4, Sox2, Klf4 and c-myc as retroviruses or lentiviruses. iPS lines will be derived based on cell morphology and pluripotency marker expression. These iPS cell lines will be characterized for their ability for form teratomas. Furthermore, we plan to characterize the biology of the disease in vitro by differentiating the iPS cells to form hematopoietic cell types in colony assays as well as by transplanting the differentiated cells into immunodeficient mice. A database will be constructed to help track the cell lines, provide information on their characterization, and to aid distribution to the community. We then plan to develop a screening system to find small molecules or shRNAs that will rescue the disease phenotype in vitro. These chemicals or genes will help understand the biology of the disease, establishing the pathogenesis and ultimately finding new therapies. Furthermore, this work should pave the way for the use of iPS cells for the study of other organ systems.

描述（由申请人提供）：罕见血液疾病患者的评估揭示了生物学，病理生理学和治疗的基本方面。最近已经分离出几种罕见遗传疾病的受影响基因，包括Diamond Blackfan贫血、Shwachman Diamond综合征和Fanconi贫血。这些疾病的动物模型的推导已被证明是困难的，因为小鼠突变表型在许多情况下确实接近人类疾病。在这里，我们建议从患有遗传性血液病（包括上述疾病和唐氏综合症）的患者身上培养人类iPS诱导的多能细胞系。我们计划从患者身上获得成纤维细胞，并引入Oct4、Sox2、Klf4和c-myc作为逆转录病毒或慢病毒。iPS系将基于细胞形态和多能性标记的表达而衍生。这些iPS细胞系将以其形成畸胎瘤的能力为特征。此外，我们计划在体外通过集落实验将iPS细胞分化成造血细胞类型，并将分化的细胞移植到免疫缺陷小鼠体内，来表征该疾病的生物学特性。将建立一个数据库，以帮助跟踪细胞系，提供有关其特征的信息，并协助向社区分发。然后我们计划开发一种筛选系统来寻找小分子或shrna，这些小分子或shrna将在体外拯救疾病表型。这些化学物质或基因将有助于了解疾病的生物学，确定发病机制并最终找到新的治疗方法。此外，这项工作将为iPS细胞用于其他器官系统的研究铺平道路。