Intergenic cis regulatory elements in the control of IL-2 and IL-21

控制 IL-2 和 IL-21 的基因间顺式调控元件

基本信息

批准号：
8656204
负责人：
ANDREW D WELLS
金额：
$ 25.2万
依托单位：
CHILDREN'S HOSP OF PHILADELPHIA
依托单位国家：
美国
项目类别：
财政年份：
2013
资助国家：
美国
起止时间：
2013-12-01 至 2015-11-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8656204
关键词：
Abscisic Acid Affect American Architecture Autoimmune Diseases Autoimmunity Binding Biological Assay Boundary Elements Bypass CD28 gene CD4 Positive T Lymphocytes Celiac Disease Cell Death Cells Chromatin Chromosomes Crohn&apos s disease Development Disease Disease susceptibility Distal Elements Engineering Enhancers Epigenetic Process Equilibrium Failure Formaldehyde Functional RNA Gene Expression Genes Genetic Genetic Transcription Genome Growth Factor Histones Homeostasis Hormones Human Human Genetics IL2 gene Immune Immune Tolerance Immune system Immunity Insulin-Dependent Diabetes Mellitus Interleukin-2 Junk DNA Ligation Link Luciferases Molecular Multiple Sclerosis Mus Natural Killer Cells Pathway interactions Plants Process Psoriasis Recombinants Regulation Regulatory Element Regulatory Pathway Regulatory T-Lymphocyte Reporter Research Retroviral Vector Rheumatoid Arthritis Risk Role Signal Transduction Simulate Single Nucleotide Polymorphism Site Stimulus Surveys T cell differentiation T memory cell T-Cell Activation T-Lymphocyte Testing Transcription Coactivator Ulcerative Colitis Work base chromatin remodeling cytokine economic impact genome wide association study interleukin-21 novel promoter public health relevance response small molecule

项目摘要

Project Summary Autoimmune disease affects over 25 million Americans, and has an economic impact of over 100 billion dollars per year. These disorders result from a break down of the intrinsic regulatory pathways that limit T cell activation and differentiation, and from a failure of regulatory T cells (Treg) to extrinsically suppress conventional T cell (Tconv) proliferation and effector function. Genetic studies in both humans and mice strongly implicate the cytokine IL-2 in the risk of developing Grave's disease, rheumatoid arthritis, celiac disease, multiple sclerosis, psoriasis, Crohn's disease, ulcerative colitis, and type 1 diabetes (T1D). The majority of the disease-associated single nucleotide polymorphisms (SNP) are located in the ~100 kb or intergenic space between the IL2 and IL21 genes, and the molecular basis for the genetic link between IL2 and autoimmunity is not understood. We have new evidence that distal, intergenic cis-regulatory elements contribute to the regulation of IL2. We find that CD28 costimulation induces looping between a distal element and the il2 promoter, and this distal element can greatly enhance IL2 transcription in promoter-reporter assays. The research proposed in this application will explore and establish the long-range regulatory architecture of the IL2 locus, paving the way for an important new understanding of the genetic basis for autoimmune disease.

项目摘要自身免疫性疾病影响超过2500万美国人，经济影响超过1000亿美元每年。这些疾病是由于限制T细胞的固有调节途径的分解而引起的激活和分化，从调节T细胞（TREG）的失败到外部抑制常规T细胞（TCONV）增殖和效应子功能。人类和小鼠的遗传研究强烈暗示细胞因子IL-2在发生坟墓疾病，类风湿关节炎，腹腔的风险中疾病，多发性硬化症，牛皮癣，克罗恩病，溃疡性结肠炎和1型糖尿病（T1D）。这大多数与疾病相关的单核苷酸多态性（SNP）位于〜100 kb或 IL2和IL21基因之间的基因间空间，以及IL2之间遗传联系的分子基础并且自身免疫尚不理解。我们有新的证据表明远端，基因间顺式调节元件有助于IL2的调节。我们发现CD28共刺激诱导远端元素之间的循环和IL2启动子，并且该远端元素可以大大增强启动子重复蛋白的IL2转录测定。本应用程序中提出的研究将探索和建立远程监管 IL2基因座的建筑，为对遗传基础的重要新理解铺平了道路自身免疫性疾病。