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

基本信息

批准号：
8486479
负责人：
George Q Daley
金额：
$ 122.99万
依托单位：
BOSTON CHILDREN'S 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 2016-04-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8486479
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&apos s Anemia Functional disorder Gene Transfer General Hospitals Generations Genes Genetic Genetic Screening Genome Stability Goals Heart Diseases Hematological Disease Hematopoietic Hematopoietic System Human In Vitro Institutes Laboratories Lesion Massachusetts Methods Modeling Morbidity - disease rate Mouse Strains Mus National Heart, Lung, and Blood Institute Nucleolar Proteins 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

项目摘要

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.

描述（由申请人提供）：我们的小组在开发用于生成多能干细胞、指导其分化为相关组织的改进技术以及 NHLBI 核心利益的两个主要系统（心血管系统和血液）的疾病建模方面有着共同的兴趣。虽然许多疾病的致病遗传病变已被确定，但某些先天性和后天性血液疾病仍然会导致显着的发病率和死亡率。动物和体外模型的局限性与造血系统尤其相关，在该系统中，将基因缺陷植入小鼠品系中未能复制范可尼贫血和唐氏综合症等疾病的主要特征。人体模型将提供一个相关的系统来研究这些疾病并开发治疗方法。我们开创了体细胞重编程方法来产生小鼠和人类诱导多能干细胞（IPS），并为胚胎干（ES）/ IPS 细胞定向分化为造血谱系带来了丰富的经验。我们希望利用这些新的“人性化”研究工具来补充我们在斑马鱼和小鼠模型方面的传统专业知识，以研究造血发育和疾病病理生理学。在本提案中，我们计划创建和研究用于遗传性血液疾病的人类 IPS 细胞，这些疾病：破坏基因组稳定性（范科尼贫血和先天性角化不良），指定异常核仁或核糖体蛋白（Shwachman-Bodian-Diamond 综合征和 Diamond-Blackfan 贫血），以及代表具有显着血液学和心脏异常（唐氏综合症）的宪法三体性。借助这些 IPS 细胞，我们将探索疾病表型，寻求基因修复策略，并寻找可能改善这些疾病的新疗法。该提案是马萨诸塞州总医院心血管研究人员 Ken Chien 和 Kit Parker 博士以及哈佛大学干细胞研究员 Doug Melton 合作 R03 应用程序的一部分，具有三个具体目标：目标#1：从患有遗传性和获得性造血系统疾病的患者中产生人类诱导多能干细胞。目标#2：探索疾病特异性 IPS 细胞的造血表型。目标#3：研究基因修复方法，并进行化学和遗传筛选，以确定新的小分子和遗传途径，以在体外改善疾病表型。