KLF10 regulates colitis through mediating TGFb induction of FOXP3 in Treg cells.

KLF10 通过介导 Treg 细胞中 TGFb 诱导 FOXP3 来调节结肠炎。

基本信息

批准号：
8423785
负责人：
William A Faubion
金额：
$ 37.06万
依托单位：
MAYO CLINIC ROCHESTER
依托单位国家：
美国
项目类别：
财政年份：
2011
资助国家：
美国
起止时间：
2011-02-15 至 2016-01-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8423785
关键词：
Address Adoptive Transfer Affect Antigens Area Autoimmune Diseases Binding Biology Cancer Prognosis Cell Line Cells Chromatin Chronic Clinic Colitis Colorectal Cancer Crohn&apos s disease DNA Data Development Diabetes Mellitus Disease Environment Enzymes Epigenetic Process Equilibrium Event Experimental Designs Experimental Models Family Family member Gene Activation Gene Expression Gene Expression Regulation Gene Targeting Generations Genes Genetic Transcription Genome Genomics Goals Histone Acetylation Histones Human Immune Immune response Immunology Inflammation Inflammatory Inflammatory Bowel Diseases Intestines Laboratories Luciferases Malignant Neoplasms Mediating Methodology Mus Neoplasms Pathogenesis Pathway interactions Predisposition Prevalence Process Protein Family Proteins Public Health Qualifying Recruitment Activity Regulation Regulatory Pathway Regulatory T-Lymphocyte Reporter Research Personnel Rheumatoid Arthritis Role Severities System T-Lymphocyte T-Lymphocyte Subsets Testing Therapeutic Transfection Transgenic Animals Transgenic Organisms Work Zinc Fingers base body system cell type chromatin modification chromatin remodeling cytokine design experience lifetime risk member novel prevent programs promoter public health relevance resistance mechanism transcription factor

项目摘要

DESCRIPTION (provided by applicant): The protein FOX3 acts on the DNA of T cells important to immune regulation. Researchers have suspected that this critical FOXP3+ T cell is important in at least the top three most common human autoimmune diseases and the four most deadly cancers. As there are over 8.5 million U.S. residents with an autoimmune disease, it is easy to appreciate the importance of understanding the mechanisms behind the development of this critical FOXP3+ T cell. Our long-term goal is to understand how the cytokine TGF, an extremely important cytokine to the intestinal environment, regulates the generation of these FOXP3+ T cells in the intestine. Our laboratory has discovered that the deficiency of a KLF family member in mice results in a block in intestinal FOXP3+ T cell generation and a tendency to develop colitis similar to human inflammatory bowel disease. Thus, our objective in this application is to determine the mechanism by which KLF family proteins mediate TGF-dependent Foxp3 gene transcription, and how disruption of this pathway leads to colitis. The three specific aims designed to achieve this objective include: (1) Test the hypothesis that KLF10 expression in T cells mediates a mechanism of resistance to colitis, (2) Test the hypothesis that KLF10 regulates distinct genomic control regions of Foxp3, and (3) Test the hypothesis that KLF10 works via distinct chromatin remodeling required for Foxp3 activation. We will use the KLF10-deficient mouse colony and adoptive transfer of immune cell compartments to determine the precise cell type in which KLF10 is critically required to prevent colitis. Subsequent TCR transgenic animals will be used to determine the mechanism by which KLF10 regulates the development of intestinal FOXP3+ T regulatory cells specific for a defined gut antigen. Human T cells lines and transient transfection methodology will be used to characterize the specific regulatory domains of KLF10 required for Foxp3 promoter function. Finally, a novel human T cell line with a defined Foxp3 promoter and luciferase reporter construct stably integrated into the host cell genome will be used to characterize KLF10-dependent chromatin modifications required for Foxp3 promoter activation. This project is significant because upon conclusion, we will understand the role for KLF10 in the regulation of Foxp3, elucidating pathobiological information into the pathogenesis of chronic inflammation and neoplasia. This in turn will stimulate new areas for experimental therapeutics in human chronic inflammatory diseases.

描述（由申请人提供）：蛋白质FOX3作用于对免疫调节重要的T细胞DNA。研究人员怀疑，这种临界FOXP3+ T细胞至少在最常见的三种最常见的人类自身免疫性疾病和四种最致命的癌症中很重要。由于有超过850万的美国居民患有自身免疫性疾病，因此很容易理解理解这种重要的FOXP3+ T细胞背后的机制的重要性。我们的长期目标是了解细胞因子TGF如何是对肠道环境极为重要的细胞因子，它如何调节肠中这些Foxp3+ T细胞的产生。我们的实验室发现，小鼠中KLF家族成员的缺乏导致肠道Foxp3+ T细胞产生的障碍，并且倾向于发展类似于人类炎症性肠病的结肠炎。因此，我们在此应用中的目标是确定KLF家族蛋白介导TGF依赖性FOXP3基因转录的机制，以及该途径的破坏如何导致结肠炎。旨在实现此目标的三个特定目的包括：（1）检验以下假设：T细胞中的KLF10表达介导了对结肠炎的抗性机制，（2）检验以下假设：KLF10调节FOXP3的不同基因组控制区域的假设，并且（3）KLF10测试KLF10通过对不同的Chromatin对Fox Fox Remodeling的不同作用。我们将使用KLF10缺乏的小鼠集落和免疫细胞室的产物转移来确定迫切需要KLF10的精确细胞类型以预防结肠炎。随后的TCR转基因动物将用于确定KLF10调节针对定义的肠道抗原特异的肠道FOXP3+ T调节细胞的发展的机制。人类T细胞系和瞬时转染方法将用于表征FOXP3启动子功能所需的KLF10的特定调节域。最后，具有定义的FOXP3启动子和荧光素酶报告基因构建体稳定整合到宿主细胞基因组中的新型人类T细胞系将用于表征Foxp3启动子激活所需的KLF10依赖性染色质修饰。该项目很重要，因为结论是，我们将了解KLF10在FOXP3调节中的作用，将病理生物学信息阐明为慢性炎症和肿瘤的发病机理。反过来，这将刺激人类慢性炎症性疾病中实验性疗法的新领域。