Costimulatory Mechanisms of Autoimmunity (Composite)

自身免疫的共刺激机制（复合）

• 批准号: 8289443
• 负责人: David A. Hafler
• 金额: $ 218.19万
• 依托单位: YALE UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 1997
• 资助国家: 美国
• 起止时间: 1997-09-01 至 2015-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8289443
• 关键词: 5 year old; A Mouse; Accounting; Address; Affect; Alleles; Antigen-Presenting Cells; Applications Grants; Autoimmune Diseases; Autoimmune Process; Autoimmunity; B-Lymphocytes; Backcrossings; Binding; Biological; Blood; Blood donor; Blood specimen; Boston; Breeding; CD28 gene; CD4 Positive T Lymphocytes; CD58 gene; CD8B1 gene; CTLA4 gene; Candidate Disease Gene; Cell Line; Cell physiology; Cell surface; Cells; Child; Chromosome Mapping; Chromosomes; Clinical Trials; Collaborations; Complex; Congenic Strain; Cytoplasmic Tail; Data; Data Analyses; Dendritic Cells; Development; Diagnosis; Disease; Disease Pathway; Drug Delivery Systems; Early identification; Engineering; Environment; Equilibrium; Etiology; Event; Exons; Family; Frequencies; Future; Genes; Genetic; Genetic Variation; Genotype; Goals; Grant; Green Fluorescent Proteins; Health Care Costs; Hereditary Disease; Homeostasis; Human; Human Genome; IL2 gene; IL2RA gene; Immune; Immune system; Immunologics; Immunophenotyping; Inbred NOD Mice; Incidence; Inflammatory; Inherited; Instruction; Insulin-Dependent Diabetes Mellitus; Interferon Type II; Interleukin-2; Introns; Investigation; Laboratories; Lead; Length; Lentivirus Vector; Ligand Binding; Ligands; Link; Literature; Mediating; Memory; Messenger RNA; Modeling; Molecular; Morbidity - disease rate; Mus; Nucleotides; PTPN22 gene; Pathway interactions; Patients; Phenotype; Phosphoric Monoester Hydrolases; Population; Predisposition; Principal Investigator; Probability; Production; Property; Protein Isoforms; Proteins; RNA Splicing; Reading; Receptor Signaling; Receptors, Antigen, B-Cell; Regulation; Regulatory T-Lymphocyte; Reporting; Research; Research Personnel; Resistance; Resources; Role; Scanning; Signal Pathway; Signal Transduction; Site; T-Cell Activation; T-Cell Receptor; T-Lymphocyte; T-Lymphocyte Subsets; Testing; Time; Transgenic Mice; Transgenic Organisms; Translating; Transmembrane Domain; Trust; Universities; Up-Regulation; Variant; base; case control; congenic; cytokine; disorder risk; gain of function; gene interaction; genetic variant; genome wide association study; healthy volunteer; in vivo; monocyte; mortality; mouse genome; mouse model; novel therapeutic intervention; overexpression; protein expression; receptor-mediated signaling; research study; response

DESCRIPTION (provided by applicant): PROJECT SUMMARY (See instructions): This renewal application builds upon significant advances in identifying both the genetic basis for autoimmune diseases and discoveries related to the function of costimulatory pathways. As part of this PPG we have defined the immunologic roles of critical costimulatory pathways implicated in the etiology of human autoimmune diseases, focusing on MS and T1D, allowing the identification and molecular characterization of a number of critical costimulatory pathways including B7/CD28, CTLA-4, CD226, ICOS, PD-L1/2 and CD2/CD58 family molecules. The application of genome wide scans to the investigation of these diseases has finally allowed a mechanistic assessment of critical costimulatory pathways based on the unbiased identification of gene variants associated with disease risk. Considering these findings, we will continue to investigate allelic variants and their pathways that are both common (CD226/TIGIT) and unique (CTI_A4-T1D and CDS-MS) to these diseases exploring the underlying hypothesis of this grant that allelic variants in multiple costimulatory pathways lead to a shift from regulatory to inflammatory T cell function. We will explore the costimulatory and signaling pathways identified from genome wide association scans in relationship to regulatory T cell and effector function, investigating the PTPN22, CTLA-4/CD28, CD226/TIGIT, and CDS pathways. This will be accomplished by three approaches: first, we will investigate the immunologic function of these allelic variants in healthy subjects who are not burdened with the inflammatory consequences of autoimmune disease; second, we will directly study patients with MS and T1D, applying our new understanding of disease pathways leading to disease risk in attempts to develop new therapeutic approaches; third; we will study the functional impact of these pathways in mouse models, focusing on how these pathways regulate the functions of effector and regulatory T cells. These goals will be accomplished with four Projects from Harvard and Cambridge Universities with an Administrative Core. RELEVANCE (See instructions): Autoimmune diseases are complex genetic disorders where many common allelic variations lead to disease risk. This understanding is key to developing new therapies. We have elucidated key pathways by performing association scans in patients with MS and Tl D. This grant will translate those genotypic findings to a fundamental understanding of immune phenotypes to identify pathways for future drug targeting. PROJECT 1: Title: - Fuctional Analyses Of Autoimmune Disease Variants Project Leader: Wicker, L PROJECT 1 DESCRIPTION (provided by applicant): PROJECT SUMMARY (See instructions): The project, Functional Analyses of Autoimmune Disease Variants, is focused on three type 1 diabetes (T1D) susceptibility loci, CTLA4, PTPN22 and CD226 in humans and in mice. T1D is a major disease of children with an unexplained steady rise in incidence and increasing numbers of children diagnosed under age 5 years. The research proposed is fully integrated into the PPG activities and goals, and provides a platform to continue the highly productive, interdependent and synergistic collaboration amongst the Pis in Cambridge and Boston aimed at understanding the biological effects of T1D and autoimmune disease gene variants (that we have identified using genetic mapping). T l D gene variants will be studied ex vivo using fresh blood samples from a major resource of genetically-selectable, local healthy volunteers (the Cambridge BioResource) and in vivo, in precisely engineered NOD mouse models of T1D. The Ctla4, Ptpn22 and Cd226 KO alleles will be used to develop NOD strains to model human T1D. A mouse Ptpn22 variant that increases T1D will be a focus of mechanistic studies on the PTPN22 gene, which is part of a molecular pathway that affects multiple human autoimmune diseases. T cells having the susceptibility allele at Ptpn22 have a higher threshold of activation and at a population level fewer of the cells produce IL-2 when stimulated ex vivo. Since both human and mouse gene variants in the IL-2 pathway affect T1D susceptibility, experiments to study gene-gene interactions between the PTPN22 and IL-2 pathways in both species are proposed. Preliminary data indicate that the susceptibility allele at CTLA4, which decreases the expression of soluble CTLA-4, reduces the probability that Tregs will be activated. Overexpression of soluble CTLA-4 in primary T cells and cell lines will be one approach used to study the mechanism by which soluble CTLA-4 affects early events in T cell activation. Since variants at both the PTPN22 and CTLA-4 genes are proposed to alter T cell activation, gene-gene interactions between the PTPN22 and CTLA-4 pathways in both humans and mice will be investigated. RELEVANCE (See instructions): The mortality, morbidity and healthcare costs of type 1 diabetes are enormous. The identification of the genes and pathways that cause type 1 diabetes will allow the identification of early, inherited immunophenotypes or disease precursors that precede autoimmunity and that may be suitable targets or read-outs in ongoing or future clinical trials.

描述（由申请人提供）： 项目摘要（请参阅说明）：此续签应用在识别自身免疫性疾病的遗传基础和与Costimulation Pathways功能相关的发现的遗传基础上的重大进展。作为该PPG的一部分，我们定义了与人类自身免疫性疾病的病因有关的关键共拟合途径的免疫学作用，重点介绍了MS和T1D，从而允许识别和分子表征许多关键的刺激途径，包括B7/CD28，CTLA-4，CTLA-4，CD226，CD226，CD2和CD2和2-L1，PD-L1，PD-L1，PD-L1，PD-L1和2-L1和2-L1和2-L1，PD-L1/2-L1和2-L1。基因组广泛扫描在对这些疾病的研究中的应用最终允许基于与疾病风险相关的基因变异的无偏鉴定，对关键的共刺激途径进行机械评估。考虑到这些发现，我们将继续研究这些疾病，这些疾病是常见的（CD226/Tigit）和独特的（CTI_A4-T1D和CDS-MS），以探索探索这一赠款的基本假设，以探索这种拨款的基本假设，该假设是该拨款的基本假设，即在多种cotimulation途径中的等位基因变体在多种cot虫中转移了调节性的细胞中的频道转换。我们将探索与调节性T细胞和效应子功能相关的基因组宽关联扫描所鉴定的共刺激和信号传导途径，研究PTPN22，CTLA-4/CD28，CD226/TIGIT和CDS途径。这将通过三种方法来完成：首先，我们将研究这些等位基因变体在健康受试者中的免疫功能，而这些受试者不承担自身免疫性疾病的炎症后果；其次，我们将直接研究MS和T1D的患者，应用我们对疾病途径的新理解，从而导致疾病风险开发新的治疗方法。第三;我们将研究这些途径在小鼠模型中的功能影响，重点是这些途径如何调节效应子和调节性T细胞的功能。这些目标将通过哈佛大学和剑桥大学具有行政核心的四个项目来实现。相关性（请参阅说明）：自身免疫性疾病是复杂的遗传疾病，许多常见的等位基因变异导致疾病风险。这种理解是开发新疗法的关键。我们通过对MS和TL D的患者进行关联扫描来阐明了关键途径。该赠款将将这些基因型发现转化为对免疫表型的基本了解，以识别未来药物靶向的途径。 项目1： 标题： - 自身免疫性疾病变体的授权分析 项目负责人：Wicker，L 项目1描述（申请人提供）： 项目摘要（请参阅说明）：该项目，自身免疫性疾病变体的功能分析集中在人类和小鼠中的三种1型糖尿病（T1D）易感性基因座，CTLA4，CTLA4，PTPN22和CD226上。 T1D是一种主要疾病，患有无法解释的儿童发病率稳定升高，诊断出5岁以下的儿童人数增加。提出的研究已完全集成到PPG的活动和目标中，并提供了一个平台，以继续在剑桥和波士顿的PIS之间继续高效，相互依存和协同的合作，旨在了解T1D和自身免疫性疾病基因变体的生物学效应（我们使用基因映射已经鉴定出来）。将使用来自基因可选择的局部健康志愿者（剑桥生物库）和体内的主要资源资源的新鲜血液样本来研究T L D基因变体。 CTLA4，PTPN22和CD226 KO等位基因将用于开发点头菌株以建模人类T1D。增加T1D的小鼠PTPN22变体将是对PTPN22基因的机械研究的重点，PTPN22基因是影响多种人体自身免疫性疾病的分子途径的一部分。在PTPN22处具有易感性等位基因的T细胞具有更高的激活阈值，在刺激离体刺激时，在人群水平下会产生IL-2。由于IL-2途径中的人和小鼠基因变异都会影响T1D易感性，因此提出了研究两种物种中PTPN22和IL-2途径之间基因基因相互作用的实验。初步数据表明，降低可溶性CTLA-4的表达的CTLA4的易感性等位基因降低了Treg会被激活的概率。原代T细胞和细胞系中可溶性CTLA-4的过表达将是一种用于研究可溶性CTLA-4影响T细胞激活早期事件的机制的方法。由于提出了PTPN22和CTLA-4基因的变体以改变T细胞的激活，因此将研究人类和小鼠的PTPN22和CTLA-4途径之间的基因基因相互作用。相关性（请参阅说明）：1型糖尿病的死亡率，发病率和医疗费用是巨大的。鉴定引起1型糖尿病的基因和途径将允许鉴定自身免疫性之前的早期，遗传的免疫表型或疾病前体，并且在正在进行或将来的临床试验中可能是合适的靶标或读出。