Immune Function and the Progression to Type 1 Diabetes

1型糖尿病(T1D)是一种在自身免疫破坏胰岛素产生后出现的疾病 胰腺β细胞。以前的研究，包括近120篇同行评议的文章-本P01支持的文章 目前的资助周期已经表明，患有或处于T1D风险增加的人表现出一系列先天的 以及与&gt；150风险相关基因座的基因型别相关的获得性免疫异常。事实上，这些努力 已经发现了一系列与T1D相关的免疫功能障碍，这些功能受到遗传学的强烈影响 (例如，功能突变、启动子/增强子变体、外显子使用的变化)和似乎驱动 自我融合。然而，T1D风险基因座对这些过程的复杂贡献仍很不清楚。因此，我们的 寻求更新这一P01的目的是阐明T1D相关变体在整个 基因组(项目1)，特别是(SH2B3[项目2]，人类白细胞抗原II区，SIRPG，CD226[项目3])，传递 表型和功能性免疫缺陷。拟议的研究将共同检验两个总体假设- 1)T1D风险变量的影响因组织、细胞亚群和激活状态而异；2)风险变量、细胞 应激和免疫途径缺陷是导致胰腺自身免疫破坏的关键。 导致T1D的细胞。这三个独立但互动性很强的项目在共享数据方面有着很强的历史， 使用创新技术，评估来自特征良好的人类的新鲜和冷冻样本 患有或面临T1D风险的受试者，通过两个核心设施确定：核心A-管理/样本 收购和核心B-生物库/生物统计学/生物信息学。项目1将实施我们的新胰腺切片 培养系统和TCR-重定向“阿凡达”，以评估炎症对靶器官的影响。项目 2将使用基因型选择的UFDI研究银行样本(核心B)、胰腺组织和分化基因- 编辑IPSC，询问SH2B3异型如何影响先天免疫细胞功能、T细胞激活和 通过发炎的血管运输。项目3建议研究胰腺淋巴结(PLN)、脾和 以测试T1D相关遗传风险变异改变TCR谱系和TCR谱的假设 基因表达途径以细胞和组织受限的方式进行。这些拟议的研究得到进一步的支持 由佛罗里达大学T1D研究的丰富环境提供，其中包括胰腺等资源 和来自糖尿病胰腺器官捐赠者网络(NPOD)的淋巴组织样本，互动 与包括T1D TrialNet在内的主要临床试验网络，以及与种族/遗传影响相关的特别努力 T1D异质性的血统(通过非常积极的招募工作成为可能)。预期的成功 应提供：1)对免疫和遗传影响的新见解 有助于T1D；2)与疾病易感性和自身免疫活性相关的新生物标记物 疾病；以及3)可以极大地改善开发有效的治疗方法的前景 防止和/或逆转T1D。

Type 1 diabetes (T1D) is a disorder that arises following the autoimmune destruction of insulin producing pancreatic β-cells. Previous studies, including nearly 120 peer reviewed-articles supported by this P01 over the current grant cycle, have demonstrated that individuals with or at increased-risk for T1D display a series of innate and adaptive immunological abnormalities linked to genetypes at >150 risk-associated loci. Indeed, these efforts have identified a series of immune dysfunctions associated with T1D that are strongly influenced by genetics (e.g., loss/gain of function mutations, promoter/enhancer variants, shifts in exon usage) and appear to drive autoimunity. Yet the complex contributions of T1D-risk loci to these processes remain quite unclear. Thus, our goal in seeking renewal of this P01 is to elucidate the mechanisms by which T1D-associated variants across the genome (Project 1), and specifically (SH2B3 [Project 2], HLA-II region, SIRPG, CD226 [Project 3]), impart phenotypic and functional immune defects. The research proposed will collectively test two overall hypotheses— 1) the impact of T1D-risk variants will vary by tissue, cell subset and activation state, and 2) risk variants, cellular stress, and defects in immunologic pathways are key to engender the autoimmune destruction of pancreatic - cells that results in T1D. The three separate but highly interactive Projects have a strong history of sharing data, using innovative technologies, and assessing fresh and cryopreserved samples from well characterized human subjects with or at risk for T1D, as ascertained through two Core facilities: Core A– Administrative/Sample Acquisition and Core B– Biobank/Biostatistics/Bioinformatics. Project 1 will implement our novel pancreas slice culture system and TCR-redirected “avatars” to evaluate the impact of inflammation in the target organ. Project 2 will use genotype selected UFDI Study Bank samples (Core B), pancreas tissues, and differentiated gene- edited iPSCs to interrogate how SH2B3 allotypes impact innate immune cell function, T cell activation, and trafficking through inflamed vasculature. Project 3 proposes to study pancreatic lymph node (pLN), spleen, and peripheral blood to test the hypothesis that T1D-associated genetic risk variants alter the TCR repertoire and gene expression pathways in a cell- and tissue-restricted manner. These proposed studies are further supported by the rich environment for T1D research at the University of Florida that includes resources such as pancreatic and lymphoid tissue samples from the Network for Pancreatic Organ donors with Diabetes (nPOD), interactions with major clinical trial networks including T1D TrialNet, and special efforts related to the impact of race/genetic ancestry (made possible through highly active recruiting efforts) on T1D heterogeneity. The successes expected from the proposed studies should provide: 1) novel insights into the immune and genetic influences that contribute to T1D; 2) novel biomarkers for disease susceptibility and autoimmune activity associated with the disease; and 3) could dramatically improve prospects for the development of an effective therapeutic capable of preventing and/or reversing T1D.