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Structure function studies in intestinal epithelial JAM

肠上皮JAM的结构功能研究

基本信息

批准号：
9916724
负责人：
CHARLES A PARKOS
金额：
$ 48.68万
依托单位：
UNIVERSITY OF MICHIGAN AT ANN ARBOR
依托单位国家：
美国
项目类别：
财政年份：
2002
资助国家：
美国
起止时间：
2002-05-01 至 2022-04-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/9916724
关键词：
Address Antibodies Attenuated Biochemical Biopsy Cell Line Cell Proliferation Cell Survival Cell physiology Cells Colitis Complex Crohn&apos s disease Cultured Cells Cyclophosphamide Cytoplasmic Tail Data Disease Down-Regulation Drug Delivery Systems Elements Epithelial Epithelial Cell Proliferation Epithelial Cells Epithelium Event Excision Family Family member Goals Homeostasis Human Impaired wound healing In Vitro Inflammation Inflammatory Injury Integral Membrane Protein Intestinal permeability Intestines Knockout Mice Leaky Gut Light Link Mediating Membrane Proteins Modeling Monomeric GTP-Binding Proteins Mucositis Mucous Membrane Mus Oncogenes Organ PTEN gene Pathologic Pattern Permeability Phosphoric Monoester Hydrolases Phosphorylation Play Protein Family Proteins Proteomics Proto-Oncogene Proteins c-akt Regulation Role Sampling Serine Signal Pathway Signal Transduction Signaling Molecule Specimen Structure System Tight Junctions Time Tissues Tyrosine Phosphorylation Ulcer Ulcerative Colitis Vaccines Xenopus Xenopus Proteins attenuation base beta catenin cancer risk experimental study gastrointestinal epithelium healing in vivo inflammatory disease of the intestine intestinal barrier intestinal epithelium intestinal homeostasis junctional adhesion molecule knock-down link protein member migration mutant novel novel strategies overexpression protein expression protein function response src-Family Kinases therapeutic target thymocyte tumor progression wound healing

项目摘要

ABSTRACT This proposal lends strong support to the new concept of tight junction associated proteins as key regulators of epithelial homeostasis in the intestine. It is now appreciated that tight junction (TJ) proteins are not static barrier forming units, but act as dynamic signaling centers to fine tune many critical epithelial cellular functions ranging including proliferation, migration and cell survival. Indeed, inflammatory conditions such as ulcerative colitis and crohns disease are associated with a leaky gut, epithelial proliferation and impaired wound healing/mucosal ulceration that is, in part, related to altered expression of tight junction proteins. Pertinent to this project, we have compelling evidence of the importance of TJ associated CTX proteins, junctional adhesion molecule A (JAM-A) and CAR Like Membrane Protein (CLMP), that play complementary roles in the regulation of mucosal homeostasis by promoting epithelial barrier function and downregulating IEC proliferative responses. Intriguingly, we have observed reduced JAM-A in epithelial cell-cell contacts under inflammatory conditions while CLMP expression, in contrast, is enhanced, suggesting coordinated fine tuning of CTX-dependent epithelial responses under conditions of perturbed homeostasis.The goal of this proposal is centered on elucidating fundamental mechanisms of how JAM-A and CLMP regulate crucial epithelial barrier function and cellular proliferation. In Aims 1 and 2, we will extend preliminary findings that identify new signaling elements controlling JAM-A-mediated regulation of barrier and epithelial proliferation, respectively. In aim 3, with new inducible, tissue targeted knockout mice, we will define, for the first time, the role of CLMP in regulation of epithelial barrier function and proliferation. The proposed studies will not only shed new light into mechanisms of outside-in signaling at the TJ that regulate permeability and proliferation, but may also provide new ideas for therapeutic targets with diverse applications ranging from enhanced vaccine/drug delivery to wound healing/anti-inflammation or inhibition of cancer progression.

摘要