Immune Function and the Progression to Type 1 Diabetes

免疫功能和 1 型糖尿病的进展

基本信息

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
项目类别：
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

项目摘要

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) 是一种因自身免疫性破坏产生胰岛素的疾病而出现的疾病胰腺 β 细胞的先前研究，包括近 120 篇受本 P01 支持的同行评审文章当前的资助周期已证明患有 T1D 或患 T1D 风险增加的个体表现出一系列先天性事实上，这些努力与超过 150 个风险相关位点的基因型有关。已经确定了一系列与 T1D 相关的免疫功能障碍，这些功能障碍受遗传的强烈影响（例如，功能缺失/获得突变、启动子/增强子变体、外显子使用的变化）并且似乎驱动然而，T1D 风险位点对这些过程的复杂贡献仍然相当不清楚。寻求 P01 更新的目标是阐明 T1D 相关变异在整个机体中的机制。基因组（项目 1），特别是（SH2B3 [项目 2]、HLA-II 区域、SIRPG、CD226 [项目 3]），赋予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 风险变异的影响将因组织、细胞亚群和激活状态而异，以及 2) 风险变异、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高度互动的项目有着悠久的数据共享历史，使用创新技术，评估来自特征明确的人类的新鲜和冷冻样本患有 T1D 或有患 T1D 风险的受试者，通过两个核心设施确定：核心 A – 管理/样本采集和核心 B – 生物库/生物统计学/生物信息学项目 1 将实施我们的新型胰腺切片。培养系统和 TCR 重定向“化身”来评估炎症对靶器官的影响。 2将使用基因型选择的UFDI研究库样本（核心B）、胰腺组织和分化基因- 编辑 iPSC 来探究 SH2B3 同种异型如何影响先天免疫细胞功能、T 细胞激活和项目 3 提议研究胰腺淋巴结 (pLN)、脾脏和外周血来检验 T1D 相关遗传风险变异改变 TCR 库的假设这些拟议的研究得到了进一步支持。佛罗里达大学丰富的 T1D 研究环境，包括胰腺等资源和来自糖尿病胰腺器官捐献者网络 (nPOD) 的淋巴组织样本，相互作用与包括 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血统（通过高度积极的招募工作成为可能）对 T1D 异质性的预期成功。拟议研究应提供：1）对免疫和遗传影响的新见解 2) 与疾病相关的疾病易感性和自身免疫活性的新型生物标志物疾病；3）可以极大地改善开发有效治疗方法的前景预防和/或逆转 T1D。

项目成果

期刊论文数量（221）

专著数量（0）

科研奖励数量（0）

会议论文数量（0）

专利数量（0）

Autoreactive T cell receptors with shared germline-like α chains in type 1 diabetes.

DOI：
10.1172/jci.insight.151349
发表时间：
2021-11-22
期刊：
JCI insight
影响因子：
8
作者：
Linsley PS;Barahmand-Pour-Whitman F;Balmas E;DeBerg HA;Flynn KJ;Hu AK;Rosasco MG;Chen J;O'Rourke C;Serti E;Gersuk VH;Motwani K;Seay HR;Brusko TM;Kwok WW;Speake C;Greenbaum CJ;Nepom GT;Cerosaletti K
通讯作者：
Cerosaletti K

Observing Islet Function and Islet-Immune Cell Interactions in Live Pancreatic Tissue Slices.

DOI：
10.3791/62207
发表时间：
2021-04-12
期刊：
Journal of visualized experiments : JoVE
影响因子：
0
作者：
Huber MK;Drotar DM;Hiller H;Beery ML;Joseph P;Kusmartseva I;Speier S;Atkinson MA;Mathews CE;Phelps EA
通讯作者：
Phelps EA

Diabetes Leads to Alterations in Normal Metabolic Transitions of Pregnancy as Revealed by Time-Course Metabolomics.

DOI：
10.3390/metabo10090350
发表时间：
2020-08-27
期刊：
Metabolites
影响因子：
4.1
作者：
Walejko JM;Chelliah A;Keller-Wood M;Wasserfall C;Atkinson M;Gregg A;Edison AS
通讯作者：
Edison AS

Avidity and Bystander Suppressive Capacity of Human Regulatory T Cells Expressing De Novo Autoreactive T-Cell Receptors in Type 1 Diabetes.

DOI：
10.3389/fimmu.2017.01313
发表时间：
2017
期刊：
Frontiers in immunology
影响因子：
7.3
作者：
Yeh WI;Seay HR;Newby B;Posgai AL;Moniz FB;Michels A;Mathews CE;Bluestone JA;Brusko TM
通讯作者：
Brusko TM

Nanovesicles From Lactobacillus johnsonii N6.2 Reduce Apoptosis in Human Beta Cells by Promoting AHR Translocation and IL10 Secretion.

DOI：
10.3389/fimmu.2022.899413
发表时间：
2022
期刊：
FRONTIERS IN IMMUNOLOGY
影响因子：
7.3
作者：
Teixeira, Leandro D.;Harrison, Natalie A.;da Silva, Danilo R.;Mathews, Clayton E.;Gonzalez, Claudio F.;Lorca, Graciela L.
通讯作者：
Lorca, Graciela L.