Project 2

项目2

• 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
• 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

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 导致耐受性崩溃。这些复杂的相互作用对发育和发育产生不利影响。 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- 细胞。除了人类白细胞抗原 (HLA) 区域外，还鉴定了超过 50 个基因位点： 带来不同程度的 T1D 风险。然而，这些变体改变的具体机制 免疫系统内的发育和信号传导事件的特征仍不清楚。我们的 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 疾病的表现。我们将检验以下假设：易感基因的组合 变异和异常的外在生长、生存和分化因子导致 T 细胞损失 T1D 背景下的耐受性。我们建议开展一系列目标：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）； 2) 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。后面的这些研究将采用新颖的 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。在 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 疾病发病机制。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。