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Effect of IPEX mutations on FOXP3 DNA binding and chromatin remodeling

IPEX 突变对 FOXP3 DNA 结合和染色质重塑的影响

基本信息

批准号：
8287120
负责人：
ANDREW D WELLS
金额：
$ 38.93万
依托单位：
UNIVERSITY OF PENNSYLVANIA
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/8287120
关键词：
Address Affect Antigen-Antibody Complex Autoimmune Diseases Binding Binding Proteins Biology CD4 Positive T Lymphocytes CREB1 gene Cell Fractionation Cell physiology Cessation of life Chemistry Childhood Chromatin Chromatin Remodeling Factor Chromatin Structure Clinical Treatment Complex DNA DNA Binding Deoxyribonucleases Disease EMSA Elements Enzyme-Linked Immunosorbent Assay Enzymes Experimental Models Family Gene Expression Genes Genetic Programming Genetic Transcription Goals Graft Rejection Histone Acetylation Histone Deacetylase Histones Human Hypersensitivity IL2RA gene Immune Immune Tolerance Immunoblotting In Situ In Vitro Inflammation Interleukin-2 Lead Link Mediating Methylation Modification Molecular Conformation Mus Mutate Mutation Nucleic Acid Regulatory Sequences Organ Transplantation Pathology Patients Pharmaceutical Preparations Process Promoter Regions Recruitment Activity Regulation Regulator Genes Regulatory T-Lymphocyte Site Specific qualifier value Syndrome System T-Lymphocyte T-Lymphocyte Subsets Testing Therapeutic Transcription Coactivator Transcription Factor AP-1 Transcription Regulatory Protein chromatin immunoprecipitation chromatin modification chromatin remodeling design gene induction gene repression immunocytochemistry in vivo insight member mutant novel therapeutics promoter response transcription factor

项目摘要

Humans with mutations in the foxpS gene suffer from a complex of autoimmune disorders (IPEX) that results from the lack of regulatory T lymphocytes, and leads to the eventual death of these patients in childhood. Recent studies in experimental models have established that FoxpS, which is a member of the forkhead family of DMA binding proteins, is necessary and sufficient for specification of regulatory T lymphocyte lineage choice and function, and therefore is crucial for acquired immune tolerance. Expression of FoxpS by T lymphocytes leads to the induction of genes associated with tolerance, and to the repression of genes that cause inflammation and immune pathology. The mechanisms by which FoxpS induces this genetic program, however, are not known. Regulatory T cells are also thought to be crucial for the inhibition of alloimmune responses during organ transplantation, and have been implicated in the control of autoimmune disease. An important goal in the treatment of patients with autoimmune disorders or organ transplants is to induce immunologic tolerance, and a basic understanding of the mechanisms that underly this process will likely be a prerequisite for the successful clinical treatment of these diseases. The studies proposed in this application are centered around basic questions of FoxpS transcriptional biology, and will add significantly to our understanding of how FoxpS regulates gene expression and promotes tolerance. A central tenet of these studies is that the regions of FoxpS mutated in IPEX patients are required for basic aspects of FoxpS function, and the studies herein are designed to determine these functions. The information gained from these studies will likewise lead to novel therapeutic strategies by which tolerance can be promoted in patients with autoimmune disease and organ transplants.

携带foxpS基因突变的人患有自身免疫性疾病（IPEX）