Role and Regulation of colon Trafficking Novel G-Protein Coupled Receptors

结肠贩运新型 G 蛋白偶联受体的作用和调节

基本信息

批准号：
9193634
负责人：
Aida Habtezion
金额：
$ 48.69万
依托单位：
STANFORD UNIVERSITY
依托单位国家：
美国
项目类别：
财政年份：
2016
资助国家：
美国
起止时间：
2016-01-01 至 2019-12-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/9193634
关键词：
Adverse effects Affect American Area Aryl Hydrocarbon Receptor Binding Binding Proteins Binding Sites Blood Circulation CD4 Positive T Lymphocytes Cells Characteristics Chronic Colitis Colon Coupled Dendritic Cells Development Disease Economic Burden Effector Cell Enhancers Etiology FOXP3 gene Flow Cytometry Future G-Protein-Coupled Receptors GATA3 gene GPR15 gene GTP-Binding Proteins Gene Expression Profiling Goals HIV Homeostasis Homing Human Human body Hydrocarbons Immune Immune System Diseases Infiltration Inflammatory Bowel Diseases Inflammatory Response Intestines Knowledge Lamina Propria Large Intestine Lead Leukocyte Trafficking Ligands Lymphocyte Mediating Memory Mus Orphan Pathogenesis Patients Play Process Proteins Recruitment Activity Refractory Regulation Regulatory T-Lymphocyte Role Site Skin Small Intestines T memory cell T-Lymphocyte Testing Th2 Cells Therapeutic Tissues Treatment Efficacy Ulcerative Colitis aryl hydrocarbon receptor ligand cell motility clinically significant comparative cytokine drug intolerance health economics improved novel public health relevance receptor response species difference terminally differentiated effector memory (TEM) T cells therapeutic target trafficking transcription factor

项目摘要

DESCRIPTION (provided by applicant): Topic Area and rationale: Inflammatory bowel disease (IBD) is a chronic immune disease that affects millions of Americans and has significant health and economic burden. Although the etiology of IBD remains unknown, disease pathogenesis is attributed in part to the increased infiltration and aberrant inflammatory responses of effector CD4+ T cells in the intestine lamina propria. Blocking of leukocyte trafficking has proved to be effective therapeutic strategy. However, mechanisms that govern CD4+ T cell migration to the colon have precluded colitis-selective treatment, as colon-specific trafficking molecules are poorly defined. Background & Hypothesis: We recently identified GPR15 as a T cell-expressed colon-specific trafficking receptor that plays a significant role in experimental colitis. We found high expression of GPR15 on colon Th2 cells of ulcerative colitis (UC) patients but is absent in mouse Th2 cells. In contrast to the mouse, human colon Tregs in both IBD and non-IBD patients do not seem to express GPR15. Detailed analysis of GPR15 expression in mouse versus human colon led us to identify species differences in Th2 versus Treg expression that correlated with preferential binding of Th2-associated GATA3 vs. Treg-associated Foxp3 transcription factor binding to human and mouse GPR15 enhancers, respectively. In addition to GPR15 expression on colon Th2 cells of UC, significant proportion of the GPR15+ CD4+ effector T cells in the IBD and non-IBD colons lack Th1 or Th17 cytokine expression. As a result, one of the project's goals is to further characterize the non-Th2 colon GPR15+ CD4+ effector T cells and understand their functional significance. Unlike the GATA3 binding motif, there exist two conserved binding sites for the aryl hydrocarbon receptor (AHR) in the GPR15 enhancer. Thus, our overall goal is to determine regulation of GPR15 and define T cell trafficking molecules in the human colon and compare to the mouse. In aim 1 we will characterize and define CD4+ T effector cells in the normal and inflamed human colon and test the hypothesis that GPR15+ CD4+ T effector cells represent specialized functional subset(s) in the colon under homeostasis and colitis. In aim 2 we will determine mechanisms that regulate GPR15 expression in the mouse and human, and test the hypothesis that GPR15 is AHR-regulated protein that plays a role in intestinal trafficking of effector T cells in response to AH ligands. Under aim 3 we will define dendritic cells that regulate GPR15 expression on CD4+ T effector cells in the colon and test the hypothesis that subset(s) of colon dendritic cells are efficient in priming colon homing CD4+ T effector cells. Significance & Impact: In order to develop new specific therapeutic targets and understand the pathogenesis of IBD/colitis, it is essential to elucidate the cellular mechanisms by which effector T cells gain access to the colon. The short-term impact of understanding colon T cell trafficking will be to define role and regulation of colon specific T cell trafficking receptors. The potential long-term impact is of gret clinical significance, as our studies could lead to development of colon T cell specific targets as potent new IBD therapeutics.

描述（由适用提供）：主题领域和理由：炎症性肠病（IBD）是一种慢性免疫学疾病，影响数百万美国人，并具有重大的健康和经济负担。尽管IBD的病因尚不清楚，但疾病发病机理的一部分是归因于肠道层中效应CD4+ T细胞的浸润和异常的炎症反应。封锁白细胞贩运已被证明是有效的治疗策略。但是，控制CD4+ T细胞向结肠的机制排除了结肠炎选择治疗，因为结肠特异性的运输分子的定义很差。背景与假设：我们最近将GPR15确定为T细胞表达的结肠特异性运输受体，在实验结肠炎中起重要作用。我们发现GPR15在溃疡性结肠炎（UC）患者的结肠Th2细胞上的高表达，但在小鼠Th2细胞中不存在。与小鼠相反，IBD和非IBD患者中的人类结肠似乎并未表达GPR15。小鼠与人结肠中GPR15表达的详细分析使我们确定了Th2中的物种差异与TREG表达的物种差异，该物种与Th2相关的GATA3与Treg相关的FOXP3转录因子的优先结合相关，分别与人和小鼠GPR15增强剂结合。除了在UC的结肠Th2细胞上的GPR15表达外，IBD和非IBD结肠中的GPR15+ CD4+效应T细胞的显着比例缺乏Th1或Th17细胞因子的表达。结果，该项目的目标之一是进一步表征非Th2结肠GPR15+ CD4+效应T细胞，并了解其功能意义。与GATA3结合基序不同，GPR15增强子中的芳基烃受体（AHR）存在两个保守的结合位点。这就是我们的总体目标是确定GPR15的调节并定义人类结肠中的T细胞运输分子并与小鼠进行比较。在AIM 1中，我们将在正常和发炎的人类结肠中表征并定义CD4+ T效应细胞，并检验以下假设：GPR15+ CD4+ T效应细胞代表稳态和结肠炎下结肠中的专业功能子集。在AIM 2中，我们将确定调节小鼠和人类中GPR15表达的机制，并检验了GPR15是AHR调节的蛋白质的假设，它在响应AH配体的效应T细胞的肠道运输中起作用。在AIM 3下，我们将定义结肠中CD4+ T效应细胞上GPR15表达的树突状细胞，并检验以下假设：结肠树突状细胞的子集有效地在启动结肠寄养CD4+ T效应细胞方面有效。意义与影响：为了开发新的特定治疗靶标并了解IBD/结肠炎的发病机理，必须阐明效应T细胞进入结肠的细胞机制至关重要。了解结肠T细胞运输的短期影响是定义结肠特异性T细胞运输受体的作用和调节。潜在的长期影响具有GRET临床意义，因为我们的研究可能导致结肠T细胞特定靶标的发展为潜在的新IBD疗法。