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Principal Investigator: Sarah A Dooley
Organization: MEDICAL UNIVERSITY OF SOUTH CAROLINA
Fiscal Year: 2024
Award: $44,698
Funding agency: National Institute of Diabetes and Digestive and Kidney Diseases
Project Summary/Abstract
Inflammatory bowel disease (IBD), comprising Crohn's Disease and Ulcerative Colitis, is a chronic condition
characterized by gastrointestinal inflammation. Among the IBD subtypes, Crohn’s disease is the most common,
affecting 1.6 million individuals in the United States today. The prevalence of IBD is increasing worldwide,
underscoring its significance as a major health issue. Despite being a significant healthcare and economic
burden there is no cure for the disease currently. The complex etiology of IBD involves a combination of genetic,
environmental, and immunological/microbial factors. Currently, the precise triggers of gastrointestinal
inflammation in IBD remains unclear. Recent studies highlight that patients with Crohn’s disease have increased
pathogenic bacteria levels and individuals with Crohn’s disease are more susceptible to bacterial infections.
Other studies have shown that microvilli and the proteins responsible for linking microvilli together, the
intermicrovillar adhesion complex (IMAC), are disorganized in Crohn’s disease patients. Under normal
physiological conditions, the IMAC are found at the tips of microvilli where they provide physical interactions
between neighboring protrusions. The IMAC increase the functional capacity of intestinal absorptive cells by
promoting dense packing of microvilli and by regulating microvilli length. To reach the microvilli tips, IMAC
components must be trafficked to the apical membrane and be correctly targeted to the tips of microvilli. It is well
documented that the molecular motor Myosin 7b traffics and anchors IMAC proteins from the apical membrane
to the tips of microvilli. Recent findings from our group have demonstrated that Myosin 5b is the molecular motor
responsible for trafficking IMAC proteins to the apical membrane of enterocytes. Interestingly, preliminary data
also suggests that Myosin 5b may play a role in the pathogenesis of IBD. However, there has yet to be a single
study that has investigated Myosin 5b, IMAC, and Crohn’s disease. This research proposal aims to investigate
how Myosin 5b regulates microvilli assembly in the intestine and investigate the degree of susceptibility of
microvilli exhibiting aberrant packing and size to pathogenic bacteria that are elevated in Crohn's disease
patients. We hypothesize that Crohn's disease patients have reduced Myosin 5b protein levels, leading to
mislocalization of IMAC components. We further hypothesize that the lack of IMAC delivery results in disordered
microvilli thereby increasing the susceptibility of the intestinal epithelium to bacterial insults. We will use both in
vivo and in vitro models to explore the alterations in Myosin 5b and IMAC components that occur in Crohn’s
disease (Aim 1), and how loss of Myosin 5b affects microvilli regulation, organization, and susceptibility to
bacterial insults (Aim 2). By employing Myosin 5b deficient mouse models and leveraging human Crohn’s
disease tissue, we aim to gain better understanding of the function of Myosin 5b in microvilli assembly and gain
novel insights into the pathogenesis of Crohn’s disease.
Terms: <21+ years old><ANK Domain><ANK Repeat><Acinetobacter><Actin-Activated ATPase><Actins><Activities of Daily Living><Activities of everyday life><Adhesions><Adult><Adult Human><Affect><Animal Model><Animal Models and Related Studies><Ankyrin Repeat><Ankyrin Repeat Domain><Apical><Area><Bacterial Adhesion><Bacterial Infections><Body Tissues><Brush Border><Causality><Cell Body><Cell Communication and Signaling><Cell Signaling><Cells><Chronic><Complex><Crohn disease><Crohn's><Crohn's disease><Crohn's disorder><Cytoplasm><Data><Disease><Disorder><E coli><E. coli><Early Diagnosis><Economic Burden><Enterocytes><Epithelial Cells><Epithelium><Escherichia coli><Etiology><Exhibits><Genetic><Granulomatous Enteritis><Health><Health Care Systems><Healthcare Systems><Host Defense><Human><Hydrogen Oxide><Immunochemical Immunologic><Immunologic><Immunological><Immunologically><Immunologics><Individual><Inflammation><Inflammatory><Inflammatory Bowel Diseases><Inflammatory Bowel Disorder><Intestinal><Intestines><Intracellular Communication and Signaling><K pneumoniae><K. pneumoniae><Klebsiella pneumoniae><Length><Link><Mediating><Mice><Mice Mammals><Microvilli><Microvillus><Modern Man><Molecular Motors><Movement><Mucins><Mucus Glycoprotein><Murine><Mus><Myosin ATPase><Myosin Adenosine Triphosphatase><Myosin Adenosinetriphosphatase><Myosins><Organoids><Pathogenesis><Pathogenicity><Patients><Peptide Domain><Physiologic><Physiological><Predisposition><Prevalence><Protein Domains><Proteins><Publications><Regulation><Research Proposals><Role><Scientific Publication><Signal Transduction><Signal Transduction Systems><Signaling><Stimulus><Striated Border><Surface><Susceptibility><Tertiary Protein Structure><Testing><Therapeutic Intervention><Tissues><USH1C><USH1C gene><Ulcerated Colitis><Ulcerative Colitis><United States><Water><adulthood><apical membrane><bacteria in the gut><bacteria infection><bacteria pathogen><bacterial disease><bacterial pathogen><biological signal transduction><body movement><bowel><causation><cellular microvillus><daily living function><daily living functionality><disease causation><disease subgroups><disease subtype><disorder subtype><early detection><eleocolitis><functional ability><functional capacity><gastrointestinal><gut bacteria><healthcare burden><in vitro Model><in vivo><inflammatory disease of the intestine><inflammatory disorder of the intestine><insight><intervention therapy><intestinal autoinflammation><intestinal epithelium><microbial><model of animal><mouse model><murine model><new marker><novel><novel biomarker><novel marker><nutrient absorption><pathobiont><pathogenic bacteria><protein complex><regional enteritis><social role><targeted drug therapy><targeted drug treatments><targeted therapeutic><targeted therapeutic agents><targeted therapy><targeted treatment><trafficking>