Intestinal Epithelial Tight Junction Structure-Function

肠上皮紧密连接结构-功能

基本信息

批准号：
8720748
负责人：
ASMA NUSRAT
金额：
$ 42.13万
依托单位：
EMORY UNIVERSITY
依托单位国家：
美国
项目类别：
财政年份：
2011
资助国家：
美国
起止时间：
2011-09-01 至 2015-03-15
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8720748
关键词：
Address Adherens Junction Apoptosis Cadherins Cell physiology Cleaved cell Colitis Complement Data Desmosomes Development Disease Down-Regulation Epithelial Epithelium Funding Future Gastrointestinal tract structure Goals Health Homeostasis In Vitro Inflammation Inflammatory Inflammatory Bowel Diseases Inflammatory disease of the intestine Integral Membrane Protein Intercellular Junctions Intestines JAM protein Knockout Mice Knowledge Link Lipids Mediating Modification Molecular Mucositis Mus Nature Nutrient Peptide Hydrolases Permeability Pharmaceutical Preparations Physiological Play Process Property Protein Dynamics Proteins Regulation Role Series Signal Pathway Signal Transduction Signaling Molecule Signaling Protein Structure Surface Therapeutic Therapeutic Agents Therapeutic Intervention Tight Junctions Tissues Toxin Transcriptional Regulation base cancer therapy cytokine desmocollin desmoglein 2 in vivo insight intestinal epithelium migration novel pathogen prevent protein expression research study uptake vaccine delivery

项目摘要

DESCRIPTION (provided by applicant): Inflammatory bowel diseases are characterized by intestinal inflammation, increased mucosal cytokines and compromised epithelial barrier function. Epithelial barrier function is regulated by a series of intercellular junctions that encompass the tight junction (TJ), adherens junction (AJ) and desmosomes (DMs). It is now evident that intercellular junctions are highly dynamic structures and their component proteins actively participate in regulating epithelial homeostasis. Mucosal inflammation perturbs intercellular junctions and epithelial homeostatic properties thereby resulting in epithelial barrier compromise. Our knowledge of the molecular basis of intercellular junction protein cross-talk, epithelial homeostasis and compromised epithelial barrier in intestinal inflammation is however very limited. Thus the overall goals of this proposal are to identify mechanisms by which intercellular junction proteins control epithelial homeostasis and barrier function and determine the influence of inflammation on epithelial barrier compromise. We will specifically examine the role of DM cadherins and TJ claudin proteins in regulating the intestinal epithelial barrier. The influence of pro- inflammatory cytokines, IFNg and TNFa on such regulatory processes will be determined. In addition to gaining insights into the molecular basis of intestinal epithelial barrier regulation, these studies will provide new ideas for the development of therapeutic agents that promote the intestinal epithelial barrier function and reduce mucosal inflammation. These studies will also provide insight into strategies of transiently perturbing the epithelial barrier for therapeutic drug/vaccine delivery and cancer therapy.

描述（由申请人提供）：炎症性肠病的特征是肠道炎症、粘膜细胞因子增加和上皮屏障功能受损。上皮屏障功能由一系列细胞间连接调节，包括紧密连接 (TJ)、粘附连接 (AJ) 和桥粒 (DM)。现在很明显，细胞间连接是高度动态的结构，其组成蛋白积极参与调节上皮稳态。粘膜炎症扰乱细胞间连接和上皮稳态特性，从而导致上皮屏障受损。然而，我们对肠道炎症中细胞间连接蛋白串扰、上皮稳态和受损上皮屏障的分子基础的了解非常有限。因此，该提案的总体目标是确定细胞间连接蛋白控制上皮稳态和屏障功能的机制，并确定炎症对上皮屏障损害的影响。我们将专门研究 DM 钙粘蛋白和 TJ 密蛋白在调节肠上皮屏障中的作用。将确定促炎细胞因子、IFNg和TNFa对此类调节过程的影响。除了深入了解肠上皮屏障调节的分子基础外，这些研究还将为开发促进肠上皮屏障功能和减少粘膜炎症的治疗药物提供新思路。这些研究还将深入了解短暂干扰上皮屏障的策略，以用于治疗药物/疫苗的输送和癌症治疗。