Polarity proteins and intestinal mucosal responses to inflammation and injury
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Principal Investigator: ASMA NUSRAT Organization: UNIVERSITY OF MICHIGAN AT ANN ARBOR Fiscal Year: 2024 Award: $482,628 Funding agency: National Institute of Diabetes and Digestive and Kidney Diseases Abstract The gastrointestinal epithelium plays a central role in maintaining barrier function while coordinating mucosal homeostasis and immunity. An important negative consequence of excessive inflammation, ischemia, certain infections, and other clinical conditions is mucosal epithelial injury and wounding that serves to compromise the epithelial barrier which is tightly regulated by intercellular junctions that include the tight junction (TJ) and adherens junction (AJ), collectively referred to as the Apical Junctional Complex (AJC). Proteins involved in regulating epithelial polarity such as the Crumbs family of proteins, influence organization and function of the AJC and regulate epithelial homeostasis and differentiation. Since most of studies on polarity proteins have been performed in model organisms and transformed cell lines, current knowledge of the molecular basis by which polarity proteins orchestrate intestinal epithelial barrier function and wound repair in vivo in mammals remains limited. The overall goal of this proposal is to identify how the polarity protein Crumbs 3 (CRB3) controls epithelial homeostasis, namely barrier function and wound repair in vivo using CRB3 transgenic mice and natural human and murine intestinal epithelium. Our overarching hypothesis is that CRB3 functions as a master regulator of intestinal epithelial barrier function and wound repair by controlling assembly of different adhesion-cytoskeletal modules at the plasma membrane. Knowledge gained from these studies in the short term will provide important new insights on basic mechanisms by which polarity proteins regulate the intestinal epithelial barrier and repair. In the long term, these studies will likely provide ideas for development of new therapeutic strategies aimed at strengthening the epithelial barrier and in promoting intestinal mucosal wound repair. Terms: <(TNF)-α><2-dimensional><Actins><Address><Adherens Junction><Adhering Junction><Adhesions><Adhesive Junction><Adhesives><Alimentary Canal><Anchoring Junction><Apical><Attenuated><Autoregulation><Binding><Biological Function><Biological Process><Biopsy><CTLA-8><CTLA-8 Gene><CTLA8><CTLA8 Gene><Cachectin><Cancers><Cell Attachment><Cell Communication and Signaling><Cell Junctions><Cell Locomotion><Cell Migration><Cell Movement><Cell Signaling><Cell membrane><Cell-Matrix Adhesions><Cell-Matrix Junction><Cellular Matrix><Cellular Migration><Cellular Motility><Clinical><Colon><Complex><Crohn disease><Crohn's><Crohn's disease><Crohn's disorder><Cytoplasm><Cytoplasmic Membrane><Cytoskeletal System><Cytoskeleton><Cytotoxic T-Lymphocyte-Associated Antigen 8><Cytotoxic T-Lymphocyte-Associated Antigen 8 Gene><Cytotoxic T-Lymphocyte-Associated Serine Esterase 8><Cytotoxic T-Lymphocyte-Associated Serine Esterase 8 Gene><Data><Development><Digestive Tract><Disease><Disorder><Epithelial Cells><Epithelium><Event><F-Actin><Family member><Filamentous Actin><GDP Dissociation Factor><GDP Dissociation Stimulators><GDP Exchange Factors><GDP-GTP Exchange Protein><GDP-GTP Reversing Factors><GI Tract><GTP GDP exchange factor><GTP Phosphohydrolases><GTPases><Gastrointestinal Tract><Gastrointestinal tract structure><Goals><Grant><Granulomatous Enteritis><Guanine Nucleotide Exchange Factors><Guanine Nucleotide Exchange Protein><Guanine Nucleotide Releasing Factors><Guanosine Triphosphate Phosphohydrolases><Guanosinetriphosphatases><Guanyl-Nucleotide Exchange Factor><Guanyl-Nucleotide Releasing Factor><Gut Epithelium><Homeostasis><Human><IFN-Gamma><IFN-g><IFN-γ><IFNG><IFNγ><IL-17><IL-17 Gene><IL-17A><IL-17A Gene><IL17><IL17 Protein><IL17 gene><IL17A><IL17A Gene><Immune><Immune Interferon><Immunes><Immunity><In Vitro><In vivo analysis><Individual><Infection><Inflammation><Inflammation Mediators><Inflammatory><Inflammatory Bowel Diseases><Inflammatory Bowel Disorder><Injury><Integral Membrane Protein><Intercellular Junctions><Interferon Gamma><Interferon Type II><Interleukin 17 (Cytotoxic T-Lymphocyte-Associated Serine Esterase 8)><Interleukin 17 (Cytotoxic T-Lymphocyte-Associated Serine Esterase 8) Gene><Interleukin 17 Precursor><Interleukin 17 Precursor Gene><Interleukin-17><Intestinal><Intestinal Mucosa><Intestines><Intracellular Communication and Signaling><Intrinsic Membrane Protein><Invertebrata><Invertebrates><Ischemia><Knowledge><Link><Macrophage-Derived TNF><Malignant Neoplasms><Malignant Tumor><Mammalia><Mammals><Mechanics><Mediating><Membrane><Merlin><Mice><Mice Mammals><Modeling><Modern Man><Moesin-Ezrin-Radixin-Like Protein><Molecular><Molecular Interaction><Monocyte-Derived TNF><Mucosa><Mucosal Tissue><Mucous Membrane><Murine><Mus><NF2><NF2 Gene Product><NF2 gene><Neurofibromatosis 2 Gene Product><Neurofibromatosis 2 Genes><Neurofibromatosis Type 2 Protein><Neurofibromin 2><Occluding Junctions><Operative Procedures><Operative Surgical Procedures><Pathogenesis><Pathologic><Peptide Domain><Persons><Physiological Homeostasis><Plasma Membrane><Play><Progenitor Cells><Protein Domains><Protein Family><Proteins><Reagent><Recovery><Regulation><Regulatory Protein><Role><Scaffolding Protein><Schwannomerlin><Schwannomin><Schwannomin Protein><Signal Transduction><Signal Transduction Systems><Signaling><Surgical><Surgical Interventions><Surgical Procedure><TNF><TNF A><TNF Alpha><TNF gene><TNF-α><TNFA><TNFα><Tertiary Protein Structure><Tight Junctions><Transformed Cell Line><Transgenic Mice><Transmembrane Protein><Transmembrane Protein Gene><Tumor Necrosis Factor><Tumor Necrosis Factor-alpha><Wound Repair><Zonula Occludens><alimentary tract><apical membrane><attenuate><attenuates><biological signal transduction><bowel><cartilage link protein><cell motility><cytokine><developmental><digestive canal><eleocolitis><epithelial injury><epithelial repair><epithelial wound><exchange factor><experiment><experimental research><experimental study><experiments><gastrointestinal epithelium><genetic regulatory protein><guanosinetriphosphatase><healing><in vivo><in vivo evaluation><in vivo testing><inflammatory disease of the intestine><inflammatory disorder of the intestine><inflammatory mediator><injuries><insight><intestinal autoinflammation><intestinal barrier><intestinal epithelium><intestinal mucosal barrier><intracellular skeleton><knock-down><knockdown><lFN-Gamma><link protein><malignancy><mechanic><mechanical><membrane structure><migration><model organism><neoplasm/cancer><new therapeutic approach><new therapeutic intervention><new therapeutic strategies><new therapy approaches><new treatment approach><new treatment strategy><nf 2 Genes><novel><novel therapeutic approach><novel therapeutic intervention><novel therapeutic strategies><novel therapy approach><plasmalemma><protein complex><protein expression><recruit><regional enteritis><regulatory gene product><repair><repair model><repaired><response><rho><rho G-Proteins><rho GTP-Binding Proteins><rho GTPases><rho Protein P21><rho Small GTP-Binding Proteins><social role><stem cells><surgery><tissue wound><two-dimensional><wound><wound closure><wound healing><wound recovery><wound resolution><wounding><wounds>