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Deciphering the role of Claudin-23 in regulation of the intestinal epithelial barrier

解读 Claudin-23 在肠上皮屏障调节中的作用

基本信息

批准号：
10646214
负责人：
Kristen Michelle Lozada-Soto
金额：
$ 4.28万
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：
2022
资助国家：
美国
起止时间：
2022-09-01 至 2024-09-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10646214
关键词：
Actins Active Sites Adherent Culture Antigens Apical Binding Sites Biochemical Biological Assay Biopsy Cell Line Cell membrane Cell physiology Cells Cellular biology Chronic Colon Complement Complex Cytoplasm Cytoskeleton DNA Binding Data Development Digestive System Disorders Disease Down-Regulation Economic Burden Environmental Risk Factor Epithelial Cells Epithelium Etiology Event Family Family member Functional disorder Gastrointestinal Diseases Genetic Predisposition to Disease Genetic Transcription Goals HIF1A gene Health Healthcare Systems Homeostasis Human Hypoxia Hypoxia Inducible Factor Immune In Vitro Inflammation Inflammatory Inflammatory Bowel Diseases Integral Membrane Protein Intercellular Junctions Intestines Investigation Knock-out Knockout Mice Knowledge Lateral Link Membrane Messenger RNA Modeling Molecular Mucous Membrane Mus Nutrient Oral Pathologic Patients Permeability Physicians Physiological Positioning Attribute Property Proteins Quality of life Reagent Regulation Role Scaffolding Protein Scientist Signal Transduction Spatial Distribution Specificity Stimulus Techniques Therapeutic Intervention Tight Junctions Tissues Training base career chromatin immunoprecipitation colonic crypt differential expression disease mechanisms study fluorescein isothiocyanate dextran gastrointestinal symptom gut homeostasis in silico in vivo intestinal barrier intestinal crypt intestinal epithelium knock-down mRNA Expression member monolayer murine colitis normoxia novel novel therapeutic intervention overexpression promoter protein expression seal tool transcription factor uptake villin

项目摘要

PROJECT SUMMARY Intestinal epithelial cells (IECs) constitute a selective barrier that regulates nutrient uptake and restricts antigen access from the lumen to the underlying mucosa. Permeability across the intestinal epithelium is dynamically regulated by a range of physiologic and pathologic stimuli. Patients with chronic inflammatory bowel disease (IBD), suffer from debilitating gastrointestinal symptoms that significantly impact their quality of life and pose a disproportionately large economic burden on the healthcare system. Although genetic susceptibility, environmental factors, and immune dysregulation are all critical contributors to the multifactorial etiology of IBD, there is increasing evidence suggesting a central role for intestinal epithelial barrier dysfunction in IBD patients. Intestinal barrier properties are regulated through dynamic remodeling and maturation of intercellular junctions along the lateral membrane of IECs. Tight junctions (TJs) are the most apical intercellular junctional complex and are composed of a highly organized array of transmembrane proteins and cytoplasmic scaffolding proteins that anchor the complex to the actin cytoskeleton. The claudin (CLDN) family of TJ transmembrane proteins is comprised of 27 members in humans that control barrier function by regulating the sealing properties of the TJ. In the colon, CLDNs are differentially expressed to spatially regulate barrier properties. Notably, CLDN expression is perturbed in IBD and has been linked to barrier compromise. However, the mechanisms by which IECs differentially express CLDNs to control barrier function and how CLDN dysregulation contributes to epithelial barrier compromise in IBD remain unclear. In this proposal we present compelling preliminary data implicating CLDN23, an understudied non-classical claudin family member, as a central orchestrator of CLDN complex stability and TJ barrier function in IECs. Moreover, we have observed that CLDN23 expression is dysregulated in IBD. Thus, my proposed studies will employ novel tools to investigate how CLDN23 controls intestinal epithelial barrier function using complementary in vitro and in vivo techniques. Successful completion of the proposed studies will expand our knowledge of basic mechanisms that control intestinal epithelial barrier function in health and disease, and will open new avenues for investigation of therapeutic interventions to restore barrier properties and ameliorate inflammation in IBD. Importantly, this scientific proposal and training will position me for a sustained career as a physician-scientist studying the mechanisms of disease of gastrointestinal inflammatory illnesses.

项目总结