Customized stem cells for clinical application in blood disorders

定制干细胞用于血液疾病的临床应用

• 批准号: 8335194
• 负责人: JAMES J COLLINS
• 金额: $ 126.77万
• 依托单位: BOSTON CHILDREN'S HOSPITAL
• 依托单位国家: 美国
• 财政年份: 2011
• 资助国家: 美国
• 起止时间: 2011-09-19 至 2014-07-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8335194
• 关键词: Address; Autologous; Biological; Biomechanics; Biomedical Engineering; Bone Marrow; Cell Transplants; Cell model; Cells; Chemicals; Clinical; Clinical Trials; Collaborations; Computational algorithm; Data; Derivation procedure; Development; Disease; Disease model; Embryo; Failure; Gene Expression; Genetic; Genotype; Goals; Hematological Disease; Hematopoietic; Hematopoietic Stem Cell Transplantation; Hematopoietic stem cells; Hemoglobinopathies; Home environment; Human; Immune; Immunologics; In Vitro; Infection; Intravenous infusion procedures; Knowledge; Lymphoid; Malignant - descriptor; Marrow; Minority; Mission; Modeling; Monoclonal Antibody R24; Mus; Pathway interactions; Patients; Phenotype; Pluripotent Stem Cells; Population; Preclinical Drug Evaluation; Principal Investigator; Production; Protocols documentation; Research; Stem cell transplant; Stem cells; Testing; Therapeutic; Therapeutic Studies; Transgenes; Transplantation; Zebrafish; adverse outcome; clinical application; clinically relevant; drug development; gene correction; gene discovery; gene repair; graft vs host disease; induced pluripotent stem cell; insight; leukemia; loss of function; morphogens; mortality; novel; progenitor; stem; stem cell population; success; transcription factor

DESCRIPTION (provided by applicant): This proposal brings together an interdisciplinary team of collaborators to address a major challenge: to achieve clinical utility of patient-specific induced pluripotent stem cells (iPSCs) for blood diseases. Our ultimate goal is to differentiate customized iPSCs into hematopoietic stem and progenitor cells to accurately model human blood diseases for research into disease mechanisms, and as a platform for treating patients with blood diseases. To achieve this, this proposal aims to discover the developmental pathways and biomechanical principles that drive the formation of hematopoietic stem cells (HSCs) in embryos, and will screen for morphogens and chemicals that promote hematopoietic maturation in vitro. We will take several novel and integrated approaches including: 1) application of predictive computational algorithms to gene expression data from highly purified embryonic HSC populations to discover the gene networks that direct hematopoietic and lymphoid development; 2) Screens in zebrafish embryos and murine and human pluripotent stem cells to discover novel chemical and biological regulators of HSCs; 3) bioengineered platforms for production of hematopoietic stem and progenitor populations, applying biomechanical forces to mimic the embryonic microenvironment; 4) derivation of iPSC from patients with Primary Immune Deficiency to correlate genotype with lymphoid phenotypes and to test strategies for gene repair through an "in vitro clinical trial"; and ultimately, 5) to derive transgene-free clinical-grade pluripotent stem cells, and develop protocols for differentiation of hematopoietic populations at clinical scale. Success in generating engraftable, genetically unperturbed HSC would be a significant breakthrough that would enhance the utility of iPSC for modeling hematopoietic disease and establish a translational platform for combining gene repair with HSC transplantation therapy.

描述（由申请人提供）：该提案汇集了一个跨学科的合作者团队，以应对重大挑战：实现患者特异性诱导的多能干细胞（IPSC）的临床实用性。我们的最终目标是将定制的IPSC区分为造血茎和祖细胞，以准确地对人类血液疾病进行研究，以研究疾病机制，并作为治疗血液疾病患者的平台。为了实现这一目标，该提案旨在发现驱动胚胎中造血干细胞（HSC）形成的发育途径和生物力学原理，并将筛选出促进体外造血成熟的形态剂和化学物质。我们将采用几种新颖和综合的方法，包括：1）将预测计算算法应用于高度纯化的胚胎HSC种群的基因表达数据，以发现直接造血和淋巴发育的基因网络； 2）在斑马鱼胚胎，鼠和人类多能干细胞中筛选，以发现HSC的新型化学和生物调节剂； 3）用于生产造血茎和祖细胞种群的生物工程平台，应用生物力学力模仿胚胎微环境； 4）从原发性免疫缺乏症患者中衍生IPSC，以通过“体外临床试验”将基因型与淋巴表型相关，并测试基因修复策略；最终，5）得出无基因的临床级多能干细胞，并开​​发了以临床规模分化造血种群的方案。成功产生植入，遗传不受干扰的HSC的成功将是一个重大突破，将增强IPSC对造血疾病建模的实用性，并建立一个转化平台，用于将基因修复与HSC移植疗法相结合。