Immune Function and the Progression to Type 1 Diabetes

免疫功能和 1 型糖尿病的进展

• 批准号: 10549499
• 负责人: Todd Michael Brusko
• 金额: $ 166.69万
• 依托单位: UNIVERSITY OF FLORIDA
• 依托单位国家: 美国
• 财政年份: 1997
• 资助国家: 美国
• 起止时间: 1997-09-30 至 2028-05-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10549499
• 关键词: Address; Age; Antigens; Autoantibodies; Autoimmune; Autoimmune Diseases; Bioinformatics; Biological Markers; Biological Models; Biomedical Research; Biometry; Blood; Blood specimen; Cell Differentiation process; Cell model; Cell physiology; Cells; Cellular Stress; Clinical; Clinical Data; Clinical Trials Network; Collection; Communication; Complement; Complex; Consent; Core Facility; Cryopreservation; Cues; Data; Data Set; Databases; Defect; Development; Diabetes Mellitus; Differentiated Gene; Disease; Disease model; Disease susceptibility; Endothelial Cells; Enhancers; Environment; Enzymes; Epigenetic Process; Exons; Florida; Flow Cytometry; Gene Expression; Gene Expression Profile; Genes; Genetic; Genetic Engineering; Genetic Risk; Genome; Genotype; Goals; Grant; Heterogeneity; Human; Imaging technology; Immune; Immune System Diseases; Immune Tolerance; Immune response; Immune system; Immunologics; Immunophenotyping; In Situ; Individual; Inflammation; Inflammatory; Insulin; Insulin-Dependent Diabetes Mellitus; Intervention Trial; Islet Cell; Islets of Langerhans; Knowledge; Life Style; Link; Longevity; Lymphatic; Lymphoid Tissue; Measurement; Mediating; Modality; Molecular; Monitor; Natural History; Neighborhoods; Organ; Organ Donor; Pancreas; Pathogenesis; Pathologic; Pathway interactions; Patients; Peer Review; Peripheral; Phenotype; Process; Proteomics; Race; Recording of previous events; Recruitment Activity; Research; Resolution; Resources; Risk; SH2B gene; Sampling; Series; Serology; Site; Slice; Spleen; Structure of beta Cell of islet; System; T-Cell Activation; T-Cell Receptor Genes; T-Lymphocyte; T-cell receptor repertoire; Technology; Testing; Therapeutic Agents; Therapeutic Intervention; Tissue Sample; Tissue imaging; Tissues; Transplantation; United States National Institutes of Health; Universities; Variant; autoimmune pathogenesis; biobank; causal variant; cell killing; cell motility; data sharing; design; draining lymph node; experience; gain of function mutation; genome wide association study; human subject; human tissue; immune activation; immune function; improved; induced pluripotent stem cell; innovation; innovative technologies; insight; islet; islet cell antibody; lymph nodes; migration; molecular phenotype; mortality; novel; novel marker; peripheral blood; phenotypic data; polygenic risk score; precision medicine; preservation; prevent; programs; promoter; risk variant; sex; success; targeted treatment; therapeutically effective; tissue resource; trafficking; Address; Age; Antigens; Autoantibodies; Autoimmune; Autoimmune Diseases; Bioinformatics; Biological Markers; Biological Models; Biomedical Research; Biometry; Blood; Blood specimen; Cell Differentiation process; Cell model; Cell physiology; Cells; Cellular Stress; Clinical; Clinical Data; Clinical Trials Network; Collection; Communication; Complement; Complex; Consent; Core Facility; Cryopreservation; Cues; Data; Data Set; Databases; Defect; Development; Diabetes Mellitus; Differentiated Gene; Disease; Disease model; Disease susceptibility; Endothelial Cells; Enhancers; Environment; Enzymes; Epigenetic Process; Exons; Florida; Flow Cytometry; Gene Expression; Gene Expression Profile; Genes; Genetic; Genetic Engineering; Genetic Risk; Genome; Genotype; Goals; Grant; Heterogeneity; Human; Imaging technology; Immune; Immune System Diseases; Immune Tolerance; Immune response; Immune system; Immunologics; Immunophenotyping; In Situ; Individual; Inflammation; Inflammatory; Insulin; Insulin-Dependent Diabetes Mellitus; Intervention Trial; Islet Cell; Islets of Langerhans; Knowledge; Life Style; Link; Longevity; Lymphatic; Lymphoid Tissue; Measurement; Mediating; Modality; Molecular; Monitor; Natural History; Neighborhoods; Organ; Organ Donor; Pancreas; Pathogenesis; Pathologic; Pathway interactions; Patients; Peer Review; Peripheral; Phenotype; Process; Proteomics; Race; Recording of previous events; Recruitment Activity; Research; Resolution; Resources; Risk; SH2B gene; Sampling; Series; Serology; Site; Slice; Spleen; Structure of beta Cell of islet; System; T-Cell Activation; T-Cell Receptor Genes; T-Lymphocyte; T-cell receptor repertoire; Technology; Testing; Therapeutic Agents; Therapeutic Intervention; Tissue Sample; Tissue imaging; Tissues; Transplantation; United States National Institutes of Health; Universities; Variant; autoimmune pathogenesis; biobank; causal variant; cell killing; cell motility; data sharing; design; draining lymph node; experience; gain of function mutation; genome wide association study; human subject; human tissue; immune activation; immune function; improved; induced pluripotent stem cell; innovation; innovative technologies; insight; islet; islet cell antibody; lymph nodes; migration; molecular phenotype; mortality; novel; novel marker; peripheral blood; phenotypic data; polygenic risk score; precision medicine; preservation; prevent; programs; promoter; risk variant; sex; success; targeted treatment; therapeutically effective; tissue resource; trafficking

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.

1型糖尿病（T1D）是一种疾病，在胰岛素生产自身免疫性破坏后出现 胰腺β细胞。先前的研究，包括该P01支持的近120个同行审查的座位 当前的赠款周期已经证明，T1D风险有或在增加风险的人显示一系列先天 以及与遗传型相关的自适应免疫异常，> 150个风险相关的地方。确实，这些努力 已经鉴定出一系列与T1D相关的免疫功能障碍，这些功能受遗传学的强烈影响 （例如，功能突变，启动子/增强子变体的损失/增益，外显子使用中的变化），似乎驱动 自动免疫。然而，T1D风险基因座对这些过程的复杂贡献尚不清楚。那，我们的 寻求续订该P01的目标是阐明T1D相关变体跨整个机制 基因组（项目1），特别是（SH2B3 [Project 2]，HLA-II地区，SIRPG，CD226 [Project 3]），授予 表型和功能免疫缺陷。提出的研究将共同​​检验两个总体假设 - 1）T1D风险变体的影响会因组织，细胞子集和激活状态而异，2）风险变体，细胞 压力和免疫途径中的缺陷是导致胰腺自身免疫性破坏--的关键。 导致T1D的细胞。这三个独立但高度互动的项目具有共享数据的悠久历史， 使用创新技术，并评估来自人类特征良好的新鲜和冷冻保存样品 通过两个核心设施确定的具有T1D或有风险的受试者：核心A - 管理/样本 获取和核心B-生物库/生物统计学/生物信息学。项目1将实施我们的小说胰腺切片 培养系统和TCR还原的“化身”，以评估炎症对目标器官的影响。项目 2将使用选定的UFDI研究银行样品（核心B），胰腺组织和分化基因的基因型基因 - 编辑的IPSC询问SH2B3同种型如何影响先天免疫器功能，T细胞激活和 通过发炎的脉管系统贩运。项目3研究胰腺淋巴结（PLN），Sleen和Sleen和 外周血测试了与T1D相关的遗传风险变异的假设改变了TCR曲目和 基因表达途径以细胞和组织限制的方式。这些提出的研究得到了进一步的支持 由佛罗里达大学T1D研究丰富的环境，包括胰腺等资源 来自糖尿病（NPOD）网络网络的淋巴组织样品，相互作用 与包括T1D试验网络在内的主要临床试验网络以及与种族/遗传的影响有关的特殊工作 关于T1D异质性的祖先（通过高度积极的招募工作使得成为可能。成功预期 从拟议的研究中应提供：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性活性相关的新型生物标志物 疾病; 3）可以极大地改善能够开发有效治疗的前景 防止和/或反向T1D。