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：
9053003
负责人：
Aida Habtezion
金额：
$ 50.14万
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/9053003
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 Dendritic Cells Development Disease Economic Burden Effector Cell Enhancers Etiology 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 Refractory Regulation Regulatory T-Lymphocyte Role Site Skin Small Intestines T memory cell T-Lymphocyte Testing Th2 Cells Therapeutic Tissues Ulcerative Colitis aryl hydrocarbon receptor ligand cell motility clinically significant comparative cytokine drug intolerance health economics improved novel public health relevance receptor receptor coupling 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（由申请人提供）：主题领域和基本原理：炎症性肠病 (IBD) 是一种慢性免疫疾病，影响数百万美国人，造成严重的健康和经济负担，尽管 IBD 的病因仍不清楚，但部分归因于疾病发病机制。肠固有层中效应 CD4+ T 细胞的浸润增加和异常炎症反应已被证明是有效的治疗策略。控制 CD4+ T 细胞迁移到结肠的机制阻碍了结肠炎选择性治疗，因为结肠特异性转运分子的定义不明确。背景和假设：我们最近发现 GPR15 是一种 T 细胞表达的结肠特异性转运受体，在结肠炎中发挥重要作用。我们发现 GPR15 在溃疡性结肠炎 (UC) 患者的结肠 Th2 细胞中高表达，但在小鼠 Th2 细胞中不存在，与小鼠、人类结肠 Treg 细胞不同。非 IBD 患者似乎不表达 GPR15 对小鼠与人类结肠中 GPR15 表达的详细分析使我们确定了 Th2 与 Treg 表达的物种差异，该差异与 Th2 相关 GATA3 与 Treg 相关 Foxp3 转录因子的优先结合相关。分别与人和小鼠 GPR15 增强子结合除了 UC 结肠 Th2 细胞上的 GPR15 表达外，IBD 中也有相当比例的 GPR15+ CD4+ 效应 T 细胞。非 IBD 结肠缺乏 Th1 或 Th17 细胞因子表达，因此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，存在两种。因此，我们的总体目标是确定 GPR15 的调节并定义人类结肠中的 T 细胞运输分子并进行比较。在目标 1 中，我们将表征和定义正常和发炎的人类结肠中的 CD4+ T 效应细胞，并测试 GPR15+ CD4+ T 效应细胞代表稳态和结肠炎下结肠中的特殊功能子集的假设。将确定在小鼠和人类中调节 GPR15 表达的机制，并检验 GPR15 是 AHR 调节蛋白的假设，该蛋白在响应 AH 的效应 T 细胞肠道运输中发挥作用在目标 3 下，我们将定义调节结肠中 CD4+ T 效应细胞上 GPR15 表达的树突细胞，并测试结肠树突细胞亚群可有效启动结肠归巢 CD4+ T 效应细胞的假设。为了开发新的特异性治疗靶点并了解 IBD/结肠炎的发病机制，有必要阐明效应 T 细胞进入结肠的细胞机制。了解结肠 T 细胞运输的短期影响将是确定结肠特异性 T 细胞运输受体的作用和调节，潜在的长期影响具有重要的临床意义，因为我们的研究可能导致结肠 T 细胞特异性靶标的开发。作为有效的 IBD 新疗法。