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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.