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最相关的三种人类组织类型提供理想的血管，即造血系统、胸腺和胰腺β细胞。这些小鼠将使用人类胎儿组织进行测试和验证。其次，我们将通过定向分化来自一组T1D患者的诱导多能干细胞来产生上述三种组织类型的每一种。这些T1D组织将被移植到免疫缺陷小鼠体内，并将对小鼠进行监测，以观察自身抗体产生和β细胞自身免疫破坏的开始。这种人类T1D的小鼠模型将首次允许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的治疗途径打开了可能性。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，新的小鼠品系和定向分化方案不仅对T1D的研究有很大的帮助，而且对许多疾病的免疫学和移植医学的研究也有广泛的用途。 公共卫生相关性：这项研究将确定治疗1型糖尿病的新方法。除此之外，还将在项目过程中开发新的小鼠品系，这将对研究人类免疫学的大量研究人员大有用处。作为该项目的一部分，还将开发新的方法，将诱导的多能干细胞转化为临床上有用的细胞类型，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受伤或疾病而缺乏这些细胞的患者体内。

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.