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）：对罕见血液疾病患者的评估已经发现了生物学，病理生理学和疗法的基本方面。最近已经分离出了几种罕见遗传疾病的受影响的基因，包括钻石黑芬贫血，shwachman钻石综合征，范科尼的贫血。事实证明，这些疾病的动物模型的推导很困难，因为在许多情况下，小鼠突变体表型确实近似人类疾病。在这里，我们建议从遗传血液疾病患者（包括上面列出的疾病）开发人IPS引起的多能细胞系。我们计划从患有疾病的患者中获得成纤维细胞，并将Oct4，Sox2，Klf4和C-Myc作为逆转录病毒或慢病毒引入。 IPS线将根据细胞形态和多能标记表达得出。这些IPS细胞系的表征能够形成畸胎瘤。此外，我们计划通过区分IPS细胞在菌落测定中形成造血细胞类型以及通过将分化细胞移植到免疫缺陷的小鼠中来表征体外疾病的生物学。将构建数据库，以帮助跟踪细胞系，提供有关其表征的信息以及帮助向社区分发。然后，我们计划开发一个筛选系统，以找到可以在体外营救疾病表型的小分子或shRNA。这些化学物质或基因将有助于了解该疾病的生物学，确定发病机理并最终找到新的疗法。此外，这项工作应该为使用IPS细胞进行其他器官系统的研究铺平道路。