Autoimmunity-associated genes in new rat models: validation of human GWAS genes

新大鼠模型中的自身免疫相关基因：人类 GWAS 基因的验证

基本信息

批准号：
8072594
负责人：
Elizabeth P Blankenhorn
金额：
$ 19.37万
依托单位：
DREXEL UNIVERSITY
依托单位国家：
美国
项目类别：
财政年份：
2010
资助国家：
美国
起止时间：
2010-05-15 至 2013-04-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8072594
关键词：
Adoptive Transfer Affect Aftercare Agonist Alleles Animals Ants Autoimmune Diabetes Autoimmune Diseases Autoimmune Process Autoimmunity Beta Cell Biological Assay Breeding Candidate Disease Gene Cells Chemicals Child Clinical Code Congenic Strain DNA Dependence Diabetes Mellitus Disease Dissection Environment Environmental Risk Factor Ethical Issues Ethics Etiology Exposure to Gene Expression Gene-Modified Genes Genetic Genetic Polymorphism Genetic Research Genome Scan Genomics Genotype Haplotypes Homologous Gene Human Human Genetics Human Genome Human Identifications Immune System Diseases Immune response In Vitro Inbred Strains Rats Inbred WF Rats Individual Infection Insulin-Dependent Diabetes Mellitus Knowledge Lead Link Lymphocyte Lymphocyte Activation Maps Measurable Mediating Mind Mission Modeling Mus Neonatal Nude Rats Outcome Pancreas Parvovirus Infections Pathway interactions Patients Phenotype Play Poly I-C Population Predisposition Prevalence Protocols documentation Public Health Quantitative Trait Loci Rattus Recombinants Regulatory Pathway Reporter Reporter Genes Research Resistance Risk Rodent Rodent Model Role Siblings Structure of beta Cell of islet Susceptibility Gene T-Lymphocyte Testing Time Tissues Transcript UBD protein Ubiquitin Validation Variant Viral Virus Virus Diseases Work Youth base congenic design disorder risk environmental agent gene interaction genome wide association study high risk interest meetings member microbial novel promoter public health relevance rat parvovirus resistant strain response tool validation studies

项目摘要

DESCRIPTION (provided by applicant): Gaps in our knowledge: Recently, numerous genetic loci with the potential to initiate or perpetuate auto- immune disease have been detected, many of them found by genome-wide association studies (GWAS). However, GWAS results are sometimes difficult to interpret, and the utility of anonymous SNP association has been questioned. Genes underlying quantitative trait loci (QTL) and GWAS need verification and testing to identify the tissue and the critical functional pathways in which they act. It would be advantageous to have an excellent animal counterpart to test hypotheses about how non-MHC genes control autoimmunity unimpaired by the ethical and practical considerations of human research. Effective rodent models would be those that: (1) display the need for a susceptible allele at a GWAS homologue in the same disease, (2) have variation in expression or coding sequence of the candidate gene, so that resistant and susceptible alleles can be compared, and (3) have measurable gene-by-environment and gene-by-gene interaction that is likely necessary to promote autoimmunity in both the human and rodent populations. Our proposed model fulfils those criteria. Novelty and Risk: Type 1 diabetes (T1D) is a T cell mediated autoimmune disease, and >18 significant non- MHC diabetes-promoting associations have been discovered by GWAS. In our novel rat model of T1D with excellent clinical fidelity and an absolute dependence on environmental perturb ants, we induce T1D in response to exposure to viruses and TLR agonists. We have mapped two highly significant rat QTL to regions containing two orthologues of human GWAS gene candidates: diubiquitin (UBD or FAT10) and UBASH3A. This model meets all three criteria above for potential to study how these genes act in diabetes induction. The risk is that neither species requires a disease-linked allele of UBD or UBASH3A in diabetogenesis, and that both human and rat mapping projects have given two incorrect candidate genes. Potential breakthroughs/relevance to mission: This work will explore the manner in which UBD and/or UBASH3A creates an environment conducive to the onset of diabetes in response to viral infection in susceptible rats, and could provide a faithful model of the way the human orthologues do the same thing. Both these candidates function in the ubiquitin pathway, already implicated in T lymphocyte activation, and the UBD transcripts are also found in the pancreas. One important outcome would be to show that enhanced post-viral ubiquity-mediated degradation of key T cell or beta-cell regulatory pathway members can lead to T1D. Aim 1. Test the hypothesis that UBD and UBASH3A are T1D candidate genes in recombinant congenic rats. Aim 2: Determine if heightened UBD and/or UBASH3A gene expression after virus infection underlie the diabetes phenotype. Determine if human UBD promoters, like the rat UBD promoter, show allelic differences in promoter activity in an in vitro reporter assay. Aim 3. Determine the tissue in which the two rat diabetes loci act to initiate T1D, with mix-and-match neonatal adoptive transfer of T cells and viral induction of T1D. PUBLIC HEALTH RELEVANCE: Autoimmunity is a serious public health issue that affects nearly 20 million US residents. Type 1 autoimmune diabetes (T1D) is increasing in prevalence and decreasing in time-to-onset; new cases appear at a rate of 1/600 in US youth. Numerous genes predispose to T1D in the context of environmental factors. Our proposal is designed to develop a rat model of virus-induced T1D in which we have mapped two genes required for autoimmune destruction of the pancreatic beta cells. Each has a human diabetes-modifying orthologue. This novel rat model will allow a fresh approach to explore and study these genes and probe potential therapies 9 based on their shared ubiquitin and pathway and T cell localization.

描述（由申请人提供）：我们所知的差距：最近，已经检测到许多遗传基因座，有可能引发或永久化自动免疫疾病，其中许多是由全基因组关联研究（GWAS）发现的。但是，GWAS的结果有时很难解释，并且已经质疑匿名SNP关联的实用性。基因定量性状基因座（QTL）和GWAS需要验证和测试，以识别组织和其作用的关键功能途径。拥有出色的动物对应物来检验关于非MHC基因如何控制人类研究的道德和实际考虑对自身免疫性如何控制自身免疫性的假设将是有利的。有效的啮齿动物模型将是：（1）表明在同一疾病中GWAS同源物中易感等位基因的需求，（2）在候选基因的表达或编码顺序上具有变化，因此可以将耐药和易感等位基因进行比较，并且（3）具有可测量的基因和基因的范围和基因的启动范围。我们提出的模型符合这些标准。新颖性和风险：1型糖尿病（T1D）是T细胞介导的自身免疫性疾病，> 18个重要的非MHC糖尿病促进关联，GWAS已发现。在我们的新型T1D大鼠模型中，具有出色的临床保真度和对环境扰动蚂蚁的绝对依赖性，我们诱导T1D响应于病毒和TLR激动剂的暴露。我们已将两个高度显着的大鼠QTL绘制为包含人类GWAS基因候选两个直系同源物的区域：二硫素（UBD或FAT10）和UBASH3A。该模型符合上面的所有三个标准，以研究这些基因在糖尿病诱导中的作用。这种风险是，在糖尿病发生中，两种物种都不需要疾病连接的UBD或UBASH3A等位基因，并且人类和大鼠地图项目都给出了两个不正确的候选基因。与使命的潜在突破/相关：这项工作将探讨UBD和/或UBASH3A的方式，创造了一个有利于糖尿病发作的环境，以响应易感大鼠的病毒感染，并可以为人类矫正力做同样的事情提供忠实的模型。这两个候选者在泛素途径中起作用，已经与T淋巴细胞激活有关，并且在胰腺中也发现了UBD转录本。一个重要的结果是表明，关键T细胞或Beta细胞调节途径成员的病毒后介导的降解可能会导致T1D。 AIM 1。检验假设，即UBD和UBASH3A是重组先生大鼠中T1D候选基因。 AIM 2：确定病毒感染后的UBD和/或UBASH3A基因表达是否增强，是糖尿病表型的基础。确定像大鼠UBD启动子这样的人UBD启动子在体外报告基因测定中是否显示出启动子活性的等位基因差异。 AIM 3。确定两只大鼠糖尿病基因座作用以启动T1D的组织，并以T细胞的新生儿发育转移和T1D的病毒诱导。公共卫生相关性：自身免疫是一个严重的公共卫生问题，影响了近2000万美国居民。 1型自身免疫性糖尿病（T1D）的患病率正在增加，并且在发发时间下降；在美国青年中，新病例的速度为1/600。在环境因素的背景下，许多基因易于T1D。我们的建议旨在开发一种病毒诱导的T1D大鼠模型，其中我们绘制了两个自身免疫性破坏胰腺β细胞所需的基因。每个都有人类糖尿病改良的直系同源物。这种新型的大鼠模型将允许一种新的方法根据其共同的泛素和途径以及T细胞定位来探索和研究这些基因和探测潜在的疗法9。