Project 2

项目2

基本信息

批准号：
10204935
负责人：
Todd Michael Brusko
金额：
$ 26.7万
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 2023-05-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10204935
关键词：
Address Affect Age Age of Onset Aging Antigens Antiviral Agents Attention Attenuated Autoimmune Diseases Autoimmunity Bayesian neural network Beta Cell Bioinformatics Blood CD8B1 gene CXCR3 gene Cell physiology Cells Clinical Clinical Data Clinical Paths Cohort Studies Collaborations Complex Cytomegalovirus Cytotoxic T-Lymphocytes Data Data Set Defect Development Diabetes Mellitus Disease Disease susceptibility Environmental Risk Factor Epigenetic Process Epistatic Gene Event FOXP3 gene Family Flow Cytometry Frequencies Gene Transfer Genes Genetic Genetic Risk Genetic Transcription Genome Genotype Growth Growth Factor HLA Antigens Heterogeneity Human IGF2 gene Immune Immune signaling Immune system Immunophenotyping Individual Insulin Insulin-Dependent Diabetes Mellitus Insulin-Like Growth Factor I Interferons Investigation Knowledge Laboratories Lead Lymphocyte Lymphoid Tissue Mediating Metabolic Metadata Modeling Molecular Profiling Natural History Organ Donor Pancreas Pathogenesis Pathway Analysis Pathway interactions Patients Peripheral Phenotype Puberty Quantitative Trait Loci Race Regulation Regulatory T-Lymphocyte Research Personnel Resources Risk Sampling Series Signal Transduction Single Nucleotide Polymorphism Somatomedins Standardization Stimulus Structure of beta Cell of islet Study Subject Sum Susceptibility Gene System T-Cell Antigen Receptor Specificity T-Cell Receptor T-Cell Receptor Genes T-Lymphocyte T-cell receptor repertoire Testing Tissues Variant antigen-specific T cells autoimmune pathogenesis autoreactive T cell clinical heterogeneity cohort design disease heterogeneity disease-in-a-dish disorder control disorder risk effector T cell gene interaction genetic variant genome-wide genomic locus glycemic control high dimensionality immune activation immune function innovation machine learning algorithm member morphogens novel novel therapeutic intervention peripheral blood phenotypic biomarker phenotypic data programs response risk variant seropositive tool transcription factor

项目摘要

PROJECT SUMMARY/ABSTRACT The development of type 1 diabetes (T1D) relies on interactions between genes imparting disease susceptibility and environmental factors thought to contribute to aberrant immune activation and signaling leading to a breakdown in tolerance. These complex interactions adversely affect the development and function of the immune cells, which mediate the autoimmune destruction of insulin-producing pancreatic β- cells. In addition to the human leukocyte antigen (HLA) region, over 50 genetic loci have been identified that confer varying degrees of risk for T1D. However, the specific mechanisms by which these variants alter the development and signaling events within in the immune system remain poorly characterized. Our studies are designed to address these knowledge gaps through investigation of peripheral blood and tissues derived from a diverse cohort of study subjects (Core B). Through these investigations, we hope to gain a better understanding for how genetic risk variants influence responses to environmental stimuli (e.g., IFN1; Project 1) that lead to a large degree of heterogeneity observed in the natural history and clinical manifestations of the disease. We will test the hypothesis that a combination of susceptibility gene variants and aberrant extrinsic growth, survival, and differentiation factors lead to a loss of T cell tolerance in the context of T1D. We propose to conduct a series of Aims to: 1) identify the T1D-associated cellular and phenotypic signatures in a cross-sectional cohort of subjects with T1D, their relatives at varying degrees of risk for the disease, and controls using extensive human immunophenotyping (HIP) by flow cytometry together with genome-wide genotyping of >974K single nucleotide polymorphisms (SNPs) and sophisticated bioinformatics analyses (with Project 3); 2) determine the phenotypic and functional impact of genetic risk variants and age-associated growth factors on regulatory and effector T cell function, and 3) create T cell receptor (TCR) “avatars” with known reactivities and isogenic cellular systems to develop a “disease in a dish” model for assessing antigen-specific T cell function. These latter studies will employ novel tools including lentiviral expression systems, directed gene editing of human T cells, and the utilization of unique clinical resources to address the challenge of epistatic gene interactions in humans with T1D. In sum, data from these Aims are expected to provide essential information about the complex interactions between genetic risk, immune signaling events, and immune cell development that impact autoimmune disease pathogenesis. The development and utilization of these innovative platforms will expedite our ability to identify and test novel therapeutic interventions to halt the autoimmune destruction of β-cells in T1D.

项目概要/摘要 1 型糖尿病 (T1D) 的发展依赖于致病基因之间的相互作用易感性和环境因素被认为导致异常的免疫激活和信号传导这些复杂的相互作用会对发育和耐受性产生不利影响。免疫细胞的功能，介导自身免疫性破坏产生胰岛素的胰腺β- 除了人类白细胞抗原 (HLA) 区域外，还鉴定了 50 多个基因位点。然而，这些变异改变 T1D 的具体机制。免疫系统内的发育和信号传导事件的特征仍不清楚。研究旨在通过调查外周血液和组织来解决这些知识差距来自不同的研究对象群体（核心 B）。通过这些调查，我们希望获得更好地了解遗传风险变异如何影响对环境刺激的反应（例如 IFN1；项目 1) 导致在自然史和临床中观察到的很大程度的异质性我们将检验易感基因组合的假设。变异和异常的外在生长、生存和分化因子导致 T 细胞损失我们建议开展一系列的工作，目的是：1) 识别 T1D 相关人群。 1型糖尿病患者横断面队列中的细胞和表型特征，以及他们的亲属在不同时期的情况疾病的风险程度，并通过流程使用广泛的人类免疫表型分析 (HIP) 进行控制细胞计数以及 >974K 单核苷酸多态性 (SNP) 的全基因组基因分型复杂的生物信息学分析（项目 3）；确定表型和功能影响遗传风险变异和年龄相关生长因子对调节和效应 T 细胞功能的影响，以及 3) 创建 T细胞受体（TCR）“化身”具有已知的反应性和同基因细胞系统，可开发“疾病” 培养皿”模型用于评估抗原特异性 T 细胞功能。工具包括慢病毒表达系统、人类 T 细胞的定向基因编辑以及利用独特的临床资源来解决人类 T1D 上位基因相互作用的挑战。总之，来自这些目标的数据预计将提供有关复杂相互作用的基本信息影响自身免疫的遗传风险、免疫信号事件和免疫细胞发育之间的关系这些创新平台的开发和利用将加快我们的能力。确定并测试新的治疗干预措施，以阻止 T1D 中 β 细胞的自身免疫破坏。