Project 2

项目2

• 批准号: 10413001
• 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/10413001
• 关键词: Address; Affect; Age; Age of Onset; Aging; Antigens; 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.

项目总结/摘要 1型糖尿病（T1 D）的发展依赖于赋予疾病的基因之间的相互作用 易感性和环境因素被认为有助于异常免疫激活和信号传导 导致耐受性的崩溃。这些复杂的相互作用对发展和 免疫细胞的功能，介导产生胰岛素的胰腺β- 细胞除了人类白细胞抗原（HLA）区域之外，已经鉴定了超过50个遗传基因座， 不同程度的T1 D风险。然而，这些变异改变细胞的具体机制是， 免疫系统内的发育和信号传导事件的特征仍然很差。我们 研究旨在通过对外周血和组织的调查来填补这些知识空白 来源于不同的研究受试者队列（核心B）。通过这些调查，我们希望获得一个 更好地理解遗传风险变异如何影响对环境刺激的反应（例如，IFN 1; 项目1）导致在自然史和临床中观察到很大程度的异质性 疾病的表现。我们将检验易感基因组合 变异和异常的外源性生长、存活和分化因子导致T细胞减少， T1 D背景下的耐受性。我们建议进行一系列的目标：1）识别T1 D相关的 T1 D受试者的横截面队列中的细胞和表型特征，他们的亲属在不同的 疾病的风险程度，并使用广泛的人类免疫表型（HIP）进行控制， 流式细胞术以及> 974 K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（与项目3）; 2）确定表型和功能的影响， 遗传风险变体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，以发展“疾病”。 用于评估抗原特异性T细胞功能的“皿”模型。这些研究将采用新的 工具，包括慢病毒表达系统，人类T细胞的定向基因编辑， 独特的临床资源，以解决人类T1 D上位基因相互作用的挑战。在 总之，这些目标的数据有望提供有关复杂相互作用的基本信息 遗传风险、免疫信号事件和影响自身免疫性疾病的免疫细胞发育之间的关系 发病机理这些创新平台的开发和利用将加快我们的能力， 确定和测试新的治疗干预措施，以阻止T1 D中β细胞的自身免疫破坏。