Reconstruction of Human Type 1 Diabetes in Mice

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，我们将利用从一组T1D患者身上提取的诱导多能干细胞进行定向分化，生成上述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，观察自身抗体产生和自身免疫对β细胞的破坏。这种人类T1D小鼠模型将首次允许对自身免疫的实时发展进行详细分析，从而开辟了确定治疗该疾病的新治疗途径的可能性。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，新的小鼠品系和定向分化方案将不仅对T1D的研究有很大的用途，而且将广泛用于许多疾病的免疫学和移植医学的研究。

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.