Reconstruction of Human Type 1 Diabetes in Mice

在小鼠中重建人类 1 型糖尿病

• 批准号: 8183478
• 负责人: DOUGLAS A MELTON
• 金额: $ 230.38万
• 依托单位: HARVARD UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2011
• 资助国家: 美国
• 起止时间: 2011-09-01 至 2013-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8183478
• 关键词: Achievement; Alleles; Animal Model; Area; Autoantibodies; Autoimmune Diseases; Autoimmune Process; Autoimmunity; Beta Cell; Biological Models; Blood Cells; Cells; Communities; Development; Disease; Engraftment; Ensure; Environmental Risk Factor; Etiology; Genetic; Genotype; Goals; Hematopoietic; Hematopoietic System; Histocompatibility Testing; Human; Hyperglycemia; Immune; Immunodeficient Mouse; Immunology; Implant; In Vitro; Inbred NOD Mice; Individual; Injury; Insulin; Insulin-Dependent Diabetes Mellitus; Laboratories; Methods; Modeling; Molecular; Monitor; Mouse Strains; Mus; Natural History; Pancreas; Pathology; Patients; Phenotype; Principal Investigator; Production; Protocols documentation; Relative (related person); Research; Research Design; Research Personnel; Risk; Stimulus; Structure of beta Cell of islet; System; Testing; Therapeutic Agents; Therapeutic Intervention; Thymic epithelial cell; Thymus Gland; Time; Tissues; Transplantation; Work; autoreactive T cell; base; cell type; cytokine; diabetic; fetal; human disease; human fetus tissue; human tissue; improved; in vivo; induced pluripotent stem cell; insight; islet; mouse model; novel; novel strategies; novel therapeutics; reconstitution; reconstruction; transplantation medicine; type I diabetic

DESCRIPTION (provided by applicant): The goal of this project is to reconstruct human Type 1 diabetes in a mouse model system. This goal will be accomplished through the achievement of two specific aims. First, we will develop optimized immunodeficient mice that will provide an ideal vessel for the three human tissue types most relevant to T1D, namely the hematopoietic system, the thymus, and pancreatic beta-cells. These mice will be tested and validated using human fetal tissues. Second, we will generate each of the three tissue types listed above using directed differentiation of induced pluripotent stem cells derived from a panel of T1D patients. These T1D tissues will be implanted in the immunodeficient mice, and the mice will be monitored to observe the onset of autoantibody production and autoimmune destruction of beta-cells. This mouse model of human T1D will allow, for the first time, a detailed analysis of the development of autoimmunity in real time, thus opening the possibility of identifying novel therapeutic avenues for the treatment of the disease. This system will also be used to test the relative contributions of various risk alleles and environmental factors to the emergence of the T1D phenotype. The novel mouse strains and directed differentiation protocols developed as part of this project will be of great use not only for the study of T1D, but will be of broad use for the study of immunology and transplantation medicine across many diseases. PUBLIC HEALTH RELEVANCE: This research will identify new ways to treat Type 1 diabetes. In addition to this, new strains of mice will be developed over the course of the project that will be of great use to a large community of researchers studying human immunology. Also as a part of this project, new methods will be developed to convert induced pluripotent stem cells into clinically useful cell types, such as blood cells and insulin-producing beta- cells, which could ultimately be transplanted into patients lacking those cells due to injury or disease.

描述（由申请人提供）：该项目的目标是在小鼠模型系统中重建人类 1 型糖尿病。这一目标将通过实现两个具体目标来实现。首先，我们将开发优化的免疫缺陷小鼠，为与 T1D 最相关的三种人体组织类型（即造血系统、胸腺和胰腺 β 细胞）提供理想的血管。这些小鼠将使用人类胎儿组织进行测试和验证。其次，我们将使用源自一组 T1D 患者的诱导多能干细胞的定向分化来生成上面列出的三种组织类型中的每一种。这些T1D组织将被植入免疫缺陷小鼠体内，并对小鼠进行监测，以观察自身抗体产生的开始和β细胞的自身免疫破坏。这种人类 T1D 小鼠模型将首次能够实时详细分析自身免疫的发展，从而为确定治疗该疾病的新治疗途径提供了可能性。该系统还将用于测试各种风险等位基因和环境因素对 T1D 表型出现的相对贡献。作为该项目的一部分开发的新型小鼠品系和定向分化方案不仅对于 T1D 的研究有很大的用途，而且对于许多疾病的免疫学和移植医学的研究也有广泛的用途。 公共健康相关性：这项研究将确定治疗 1 型糖尿病的新方法。除此之外，在该项目过程中还将开发出新的小鼠品系，这对于研究人类免疫学的大量研究人员来说将有很大的用处。作为该项目的一部分，还将开发新方法将诱导多能干细胞转化为临床有用的细胞类型，例如血细胞和产生胰岛素的β细胞，这些细胞最终可以移植到因损伤而缺乏这些细胞的患者体内或疾病。

项目成果

A simple tool to improve pluripotent stem cell differentiation.

• DOI: 10.1038/nmeth.2442
• 发表时间: 2013-06
• 期刊: NATURE METHODS
• 影响因子: 48
• 作者: Chetty, Sundari;Pagliuca, Felicia Walton;Honore, Christian;Kweudjeu, Anastasie;Rezania, Alireza;Melton, Douglas A.
• 通讯作者: Melton, Douglas A.

A Src inhibitor regulates the cell cycle of human pluripotent stem cells and improves directed differentiation.

• DOI: 10.1083/jcb.201502035
• 发表时间: 2015-09-28
• 期刊: The Journal of cell biology
• 作者: Chetty S;Engquist EN;Mehanna E;Lui KO;Tsankov AM;Melton DA
• 通讯作者: Melton DA