Reprogramming of fibroblasts to pluripotency- a new tool to study Primary Immunod

成纤维细胞重编程为多能性——研究初级免疫的新工具

基本信息

批准号：
8022818
负责人：
Luigi Daniele Notarangelo
金额：
$ 8.56万
依托单位：
BOSTON CHILDREN'S HOSPITAL
依托单位国家：
美国
项目类别：
财政年份：
2010
资助国家：
美国
起止时间：
2010-04-01 至 2012-06-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8022818
关键词：
Address Affect Animal Model Autoimmune Process Autoimmunity Biological Models Boston Cell Line Cell Transplantation Cells Chronic Clinical Collaborations Collection Communities Correlation Studies Coupled DNA Repair Defect Development Disease Fibroblasts Foundations Functional disorder Future Gene Targeting Gene Transfer Generations Genes Genetic Genotype Hematopoietic Hematopoietic stem cells Hereditary Disease Heterogeneity Human Human Genome IL7R gene Immune Immune system Immunoglobulin M Immunologic Deficiency Syndromes Immunology In Vitro Infection Insertional Mutagenesis Investigation JAK3 gene Knowledge Laboratories Letters Link Lymphoid Malignant Neoplasms Mediating Methods Modality Modeling Modification Molecular Mus Mutation Myelogenous Pathology Patients Pediatric Hematology/Oncology Pediatric Hospitals Phenotype Pluripotent Stem Cells Population Pre-Clinical Model Predisposition Proteome Replacement Therapy Resistance Retroviral Vector Risk Safety Skin Sleeping Beauty Somatic Cell Source Stem Cell Development Stem cells Subgroup Syndrome Systems Development TNFRSF5 gene TNFSF5 gene Techniques Testing Thrombocytopenia Time Transplantation Transposase Viral Work Zinc Fingers base embryonic stem cell gene correction gene repair gene therapy improved induced pluripotent stem cell insight interest meetings novel novel strategies novel therapeutic intervention novel therapeutics nuclease outcome forecast pluripotency preclinical evaluation public health relevance reconstitution repository standard of care stem stemness tool transcription factor tumor

项目摘要

DESCRIPTION (provided by applicant): Primary immunodeficiencies (PIDs) comprise over 150 different diseases characterized by increased susceptibility to infections, autoimmune manifestations, and tumors. The study of human PID has been essential to identify key mechanisms that govern development and/or function of the immune system. More than 130 gene defects that are responsible for PID in humans have been identified. In addition, different mutations in the same gene have been often associated with distinct phenotypes, indicating the existence of extraordinary genetic and phenotypic heterogeneity. In spite of this progress, there is a need to better define at the cellular level the pathophysiology of several forms of PID, to perform genotype-phenotype correlation studies by analyzing, under the same experimental conditions, the differentiation potential and function of patient-derived cells carrying different mutations in the same gene, and to develop preclinical models to explore novel therapeutic strategies for PID with a severe prognosis. The use of animal models to address these objectives has significant limitations, because of the limited availability of models carrying different mutations in the same gene, and because of intrinsic differences between humans and other species. Recent advances in cell reprogramming, leading to generation of induced pluripotent stem (iPS) cells from mature somatic cells (eg, fibroblasts), now offer for the first time ever the possibility to create a valuable repository of pluripotent cells from patients carrying various mutations in PID-causing genes. Taking advantage of the availability of a large repository of fibroblast cell lines derived from patients with a variety of mutations in PID-causing genes, and of our expertise in the generation of human iPS cells, we will create a repository of iPS clones from patients with well- defined PID. We will characterize the stemness profile and pluripotency of patient-derived iPS cells, and will use genetic tools to confirm their patient-specific origin. Creation of a repository of iPS cells from patients with PID will provide the scientific community with a limitless source of progenitor cells that can be used for in vitro differentiation and genotype-phenotype correlation studies, and for preclinical evaluation of safety and efficacy of novel therapeutic strategies. We anticipate that use of this repository of iPS cells from patients with PID will help improve the knowledge and treatment of these disorders. PUBLIC HEALTH RELEVANCE: Primary immunodeficiencies (PIDs) comprise over 150 different diseases characterized by increased susceptibility to infections, autoimmune manifestations, and tumors. Availability of a limitless source of stem cells from patients with PID would be important to improve the knowledge of the mechanisms of disease and to assist in the development of novel therapeutic approaches based on correction of the gene defect. Human fibroblasts (ie, cultured skin cells) can be reprogrammed to become induced pluripotent cells (iPS) cells. Taking advantage of our expertise in generation of iPS cells and in availability of a large collection of fibroblast cell lines from patients with PID, we intend to create the first repository of iPS cells from patients with PID. We anticipate that use of this repository of iPS from patients with PID will help the scientific community improve the knowledge and treatment of these disorders.

描述（由申请人提供）：原发性免疫缺陷 (PID) 包括 150 多种不同的疾病，其特征是对感染、自身免疫表现和肿瘤的易感性增加。人类 PID 的研究对于确定控制免疫系统发育和/或功能的关键机制至关重要。已发现超过 130 种导致人类 PID 的基因缺陷。此外，同一基因的不同突变通常与不同的表型相关，表明存在非凡的遗传和表型异质性。尽管取得了这些进展，但仍需要在细胞水平上更好地定义几种形式的 PID 的病理生理学，通过在相同的实验条件下分析患者来源的细胞的分化潜力和功能来进行基因型-表型相关性研究。细胞在同一基因中携带不同突变，并开发临床前模型，探索预后严重的 PID 的新治疗策略。使用动物模型来实现这些目标具有很大的局限性，因为在同一基因中携带不同突变的模型的可用性有限，并且由于人类和其他物种之间的内在差异。细胞重编程的最新进展，导致从成熟体细胞（例如成纤维细胞）产生诱导多能干（iPS）细胞，现在首次提供了从携带各种突变的患者中创建有价值的多能细胞库的可能性。 PID 致病基因。利用源自患有多种 PID 致病基因突变的患者的成纤维细胞系的大型存储库，以及我们在生成人类 iPS 细胞方面的专业知识，我们将创建一个来自 PID 患者的 iPS 克隆存储库。明确定义的PID。我们将表征患者来源的 iPS 细胞的干性特征和多能性，并将使用遗传工具来确认其患者特异性起源。创建 PID 患者 iPS 细胞库将为科学界提供无限的祖细胞来源，可用于体外分化和基因型-表型相关性研究，以及用于新型治疗策略的安全性和有效性的临床前评估。我们预计，使用来自 PID 患者的 iPS 细胞库将有助于提高对这些疾病的认识和治疗。公共卫生相关性：原发性免疫缺陷 (PID) 包括 150 多种不同的疾病，其特征是对感染、自身免疫表现和肿瘤的易感性增加。获得来自 PID 患者的无限来源的干细胞对于提高对疾病机制的了解并协助开发基于纠正基因缺陷的新治疗方法非常重要。人类成纤维细胞（即培养的皮肤细胞）可以重新编程成为诱导多能细胞（iPS）。利用我们在 iPS 细胞生成方面的专业知识以及从 PID 患者获得的大量成纤维细胞系的可用性，我们打算创建第一个来自 PID 患者的 iPS 细胞库。我们预计，使用 PID 患者的 iPS 存储库将有助于科学界提高对这些疾病的认识和治疗。