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Regulation of Intestinal Tight Junction Barrier and Inflammation by Autophagy

自噬对肠道紧密连接屏障和炎症的调节

基本信息

批准号：
9362276
负责人：
Prashant Nighot
金额：
$ 36.58万
依托单位：
UNIVERSITY OF NEW MEXICO HEALTH SCIS CTR
依托单位国家：
美国
项目类别：
财政年份：
2017
资助国家：
美国
起止时间：
2017-09-01 至 2018-06-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/9362276
关键词：
Acids Address Animal Model Animals Antigens Apical Applications Grants Autophagocytosis Autophagosome Celiac Disease Cell Survival Clinical Data Colitis Colon Crohn&apos s disease Data Defect Degradation Pathway Development Disease Disease model Ensure Enterocolitis Epithelial Etiology Genes Goals Haptens Health Homeostasis Immune Inflammation Inflammatory Inflammatory Bowel Diseases Inflammatory disease of the intestine Interleukin-10 Intestinal Diseases Intestines Knowledge Laboratories Length Link Lysosomes MAP Kinase Gene MAPK3 gene Malignant Neoplasms Mediating Membrane Membrane Proteins Metabolic stress Modeling Molecular Mus Mutation Nerve Degeneration Nutrient Pathologic Patients Penetration Perfusion Permeability Physiological Play Predisposition Prevention Prevention therapy Process Proteins Recycling Regulation Risk Factors Role Signal Transduction Small Interfering RNA Sodium Dextran Sulfate System Technology Therapeutic Tight Junctions Vesicle Virulence Factors base cytokine frontier genome wide association study human disease human tissue in vivo innovation insight intestinal epithelium intestinal homeostasis mouse model new therapeutic target novel novel strategies occludin prevent protein transport quantitative imaging tool trafficking

项目摘要

Project Summary The long-term goal of our laboratory is to elucidate the molecular basis for intestinal homeostasis and its dysregulation in intestinal inflammation, and to develop novel approaches for prevention and therapy of inflammatory bowel diseases (IBD). The apically located inter-cellular tight junctions (TJ) within the intestinal epithelium act as a paracellular barrier and prevent permeation of noxious luminal antigens. Loss of intestinal TJ barrier function is a key pathogenic factor in intestinal disorders and IBD. Autophagy (macroautophagy) is an intracellular degradation system that delivers unnecessary or dysfunctional cellular cargo sequestered inside double-membrane vesicles (autophagosomes) to the lysosome. Emerging evidence shows that defects in autophagy play an important role in the susceptibility, etiology, and progression of IBD. Although clinical data and animal studies show a direct link between defective intestinal TJ barrier and intestinal inflammation in IBD patients and animal models of IBD, the role of autophagy in the regulation of intestinal epithelial TJ barrier remains unknown. Our preliminary studies indicated that autophagy plays a key role in the enhancement of intestinal TJ barrier. Specifically, autophagy reduces paracellular TJ permeability by degradation of the pore forming tight junction protein claudin-2 and increasing protein levels of barrier protective transmembrane TJ protein occludin. Induction of autophagy causes a selective increase in lysosomal targeting of claudin-2 from the membrane and causes an increase in membrane retention of occludin. Thus, our central hypothesis is that autophagy selectively modulates TJ membrane protein composition to induce an enhancement of the intestinal TJ barrier. We will address our hypothesis with the specific aims of (1) To delineate the intracellular vesicular trafficking mechanisms in autophagy-induced enhancement of intestinal epithelial TJ barrier; (2) To elucidate the mechanistic role of intracellular signaling in autophagy regulation of intestinal TJ barrier; and (3) To delineate the protective role of autophagy-mediated enhancement of intestinal TJ barrier function in murine models of IBD. We will use innovative technical tools such as in vivo siRNA technology, in vivo full length mice colon perfusion, in vivo intestinal TJ protein trafficking, and high content quantitative imaging to study our specific aims. This proposal will provide novel insights into the crucial role that autophagy plays in the homeostasis of intestinal barrier and bridge the gap in scientific knowledge that will be important for therapeutic efforts against IBD.

项目总结