Human Pluripotent Stem Cell and Progenitor Models of Cardiac and Blood Diseases

人类多能干细胞和心脏和血液疾病的祖细胞模型

• 批准号: 7833765
• 负责人: George Q Daley
• 金额: $ 128.25万
• 依托单位: BOSTON CHILDREN'S 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 2016-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7833765
• 关键词: Animals; Blood; Cardiac; Cardiovascular system; Cell Line; Cells; Communities; Complement; Constitutional; Defect; Derivation procedure; Development; Diamond; Diamond-Blackfan anemia; Disease; Disease model; Down Syndrome; Dyskeratosis Congenita; Embryo; Engineered Gene; Fanconi' s Anemia; Functional disorder; Gene Transfer; General Hospitals; Generations; Genes; Genetic; Genetic Screening; Genome Stability; Goals; Hematological Disease; Hematopoietic; Hematopoietic System; Human; In Vitro; Institutes; Laboratories; Lesion; Massachusetts; Methods; Modeling; Morbidity - disease rate; Mouse Strains; Mus; Pathway interactions; Patients; Phenocopy; Pluripotent Stem Cells; Research; Research Personnel; Ribosomal Proteins; Somatic Cell; Specific qualifier value; Stem cells; Syndrome; System; Techniques; Testing; Therapeutic; Therapeutic Agents; Tissues; Transgenes; Trisomy; Universities; Viral Genes; Zebrafish; chemical genetics; disease phenotype; expectation; experience; gene repair; homologous recombination; improved; in vitro Model; induced pluripotent stem cell; interest; knock-down; mortality; novel; novel therapeutics; progenitor; repository; research study; small molecule; stem; tool

DESCRIPTION (provided by applicant): Our groups have common interests in the development of improved techniques for generating pluripotent stem cells, directing their differentiation into relevant tissues, and in disease modeling in two major systems of central interest to the NHLBI-the cardiovascular system and the blood. While the causative genetic lesion has been identified for many conditions, certain inborn and acquired hematologic disorders continue to cause significant morbidity and mortality. The limitations of animal and in vitro models is particularly relevant to the hematopoietic system, where engineering gene defects into mouse strains has failed to phenocopy cardinal features of diseases like Fanconi anemia and Down Syndrome. Human models would offer a relevant system to study these diseases and to develop therapeutics. We have pioneered methods for somatic cell reprogramming to generate mouse and human induced pluripotent stem cells (IPS) and bring considerable experience to the directed differentiation of embryonic stem (ES)/ IPS cells into hematopoietic lineages. We wish to exploit these new "humanized" research tools to complement our traditional expertise in zebrafish and murine models to study hematopoietic development and disease pathophysiology. In this proposal we plan to create and study human IPS cells for genetic blood diseases that: disrupt genomic stability (Fanconi's anemia and Dyskeratosis congenita), specify aberrant nucleolar or ribosomal proteins (Shwachman-Bodian-Diamond Syndrome and Diamond-Blackfan Anemia), and represent a constitutional' trisomy with prominent hematologic and cardiac anomalies (Down Syndrome). With these IPS cells, we will explore disease phenotypes, pursue strategies for gene repair, and search for novel therapeutics that might ameliorate these conditions. This proposal is part of a collaborative R03 application with Drs Ken Chien and Kit Parker, cardiovascular researchers at the Massachusetts General Hospital, and Doug Melton, a stem cell researcher at Harvard University, and has three specific aims: Aim #1: Generate human induced pluripotent stem cells from patients with genetic and acquired disorders of the hematopoietic system. Aim #2: Explore the hematopoietic phenotypes of disease-specific IPS cells. Aim #3: Investigate methods for gene repair, and pursue chemical and genetic screening to identify novel small molecules and genetic pathways to ameliorate the disease phenotypes in vitro.

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