Fuctional Analyses of Autoimmune Disease Variants

自身免疫性疾病变异体的功能分析

基本信息

批准号：
8378754
负责人：
Linda S. Wicker
金额：
$ 41.83万
依托单位：
YALE UNIVERSITY
依托单位国家：
美国
项目类别：
财政年份：
资助国家：
美国
起止时间：
至
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/8378754
关键词：
5 year old A Mouse Address Affect Alleles Applications Grants Autoimmune Diseases Autoimmune Process Autoimmunity B-Lymphocytes Backcrossings Binding Biological Blood Blood donor Blood specimen Boston CD8B1 gene CTLA4 gene Candidate Disease Gene Cell Line Cells Child Chromosome Mapping Chromosomes Clinical Trials Collaborations Congenic Strain Data Dendritic Cells Development Diagnosis Disease Early identification Engineering Equilibrium Event Exons Frequencies Future Genes Genetic Genetic Variation Genotype Goals Health Care Costs Homeostasis Human Human Genome IL2 gene IL2RA gene Immune Immune system Immunophenotyping Inbred NOD Mice Incidence Inherited Insulin-Dependent Diabetes Mellitus Interferon Type II Interleukin-2 Laboratories Ligands Link Literature Mediating Memory Messenger RNA Modeling Molecular Morbidity - disease rate Mus PTPN22 gene Pathway interactions Phenotype Phosphoric Monoester Hydrolases Population Predisposition Probability Production Protein Isoforms Proteins RNA Splicing Reading Receptor Signaling Receptors, Antigen, B-Cell Regulation Regulatory T-Lymphocyte Reporting Research Research Personnel Resistance Resources Role Signal Transduction T-Cell Activation T-Cell Receptor T-Lymphocyte T-Lymphocyte Subsets Testing Time Transgenic Mice Transgenic Organisms Transmembrane Domain Trust Up-Regulation Variant base case control congenic gain of function gene interaction genetic variant healthy volunteer in vivo monocyte mortality mouse genome mouse model overexpression protein expression receptor-mediated signaling research study

项目摘要

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.

该项目是自身免疫性疾病变种的功能分析，集中在人类和小鼠中的三种1型糖尿病（T1D）易感基因座，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。