The role and regulation of deep crypt secretory cells in colitis

Document text

Principal Investigator: Michael Andrew Schumacher
Organization: CHILDREN'S HOSPITAL OF LOS ANGELES
Fiscal Year: 2024
Award: $157,540
Funding agency: National Institute of Diabetes and Digestive and Kidney Diseases

PROJECT SUMMARY
Deep crypt secretory (DCS) cells are an understudied lineage of secretory cells residing in the colonic crypt
base with unknown roles in colitis. In preliminary data, I show that DCS cells express a class of proteins known
as host defense peptides (HDPs) that can influence key epithelial (e.g. differentiation, barrier integrity) and
immune functions. Despite clear demonstrations of altered colonic secretory cell numbers and HDP levels in
inflammatory bowel disease (IBD), the mechanisms regulating DCS cells and HDPs are poorly understood.
This proposal is designed to identify the mechanisms driving DCS cell differentiation and HDP
production in colitis, and determine the role of these factors in regulating epithelial and immune
functions. Using a mouse model with elevated DCS cell numbers, I am proposing coordinated in vivo and in
vitro approaches to understand the mechanisms underlying DCS cell differentiation and HDP expression in the
colon (Aim 1) and to test how altered DCS cell-derived HDPs affect colonic homeostasis and acute and
chronic colitis severity (Aim 2). This work will be accomplished with new expertise obtained in advanced
transcriptomic studies and epithelial lineage tracing in models of colitis by working with my team of co-mentors
and advisory committee. This work will advance our understanding of the cellular mechanisms that drive
intestinal epithelial remodeling in colitis, and thus may reveal new potential therapeutic targets for IBD and
other intestinal inflammatory disease. The research and career development plan, generated in concert with
my mentors and advisory committee, will provide the training and support necessary to become an
independent investigator at an academic research institution.

Terms: <1-Phosphatidylinositol 3-Kinase><Acute><Advisory Committees><Affect><Area><Automobile Driving><Autoregulation><Award><Biology><Career Development Awards><Career Development Awards and Programs><Career Development Programs K-Series><Cell Body><Cell Communication and Signaling><Cell Count><Cell Differentiation><Cell Differentiation process><Cell Function><Cell Line><Cell Number><Cell Physiology><Cell Process><Cell Signaling><Cell Survival><Cell Viability><CellLine><Cells><Cellular Function><Cellular Immune Function><Cellular Physiology><Cellular Process><Cellular biology><Chronic><Colitis><Colon><Data><Development><Development Plans><Development and Research><Doctor of Philosophy><Epithelial Cells><Epithelium><Foundations><Funding><Goals><Health><Homeostasis><Host Defense><Human><IL-13><IL13><Immune><Immune Cell Activation><Immune response><Immunes><Immunoblotting><Immunological response><In Vitro><Inflammation><Inflammatory Bowel Diseases><Inflammatory Bowel Disorder><Institution><Interleukin-13><Intestinal><Intestines><Intracellular Communication and Signaling><Investigators><K-Awards><K-Series Research Career Programs><KO mice><Knock-out Mice><Knockout Mice><Mentors><Mice><Mice Mammals><Modeling><Modern Man><Murine><Mus><NIH><National Institutes of Health><Null Mouse><Organoids><PI-3 Kinase><PI3-Kinase><PI3CG><PI3KGamma><PI3k><PIK3><PIK3CG><PIK3CG gene><Pathway interactions><Patients><Peptides><Ph.D.><PhD><Phosphatidylinositol 3-Kinase><Phosphatidylinositol-3-OH Kinase><Phosphoinositide 3-Hydroxykinase><Physiological Homeostasis><Population><Principal Investigator><Production><Proteins><PtdIns 3-Kinase><R & D><R&D><Recovery><Regulation><Repression><Research><Research Career Program><Research Personnel><Researchers><Resistance><Role><Secretory Cell><Severities><Shapes><Signal Transduction><Signal Transduction Systems><Signaling><Source><Strains Cell Lines><Subcellular Process><Task Forces><Testing><Training><Type I Phosphatidylinositol Kinase><Type III Phosphoinositide 3-Kinase><United States National Institutes of Health><Western Blotting><Western Immunoblotting><Work><advisory team><base><bases><biological signal transduction><bowel><career><career development><cell biology><cellular differentiation><colonic crypt><cultured cell line><cytokine><design><designing><developmental><driving><experiment><experimental research><experimental study><experiments><gain of function><healing><host response><immune activation><immune function><immune system response><immunoresponse><in vivo><inflammatory disease of the intestine><inflammatory disorder of the intestine><inhibitor><insight><intestinal autoinflammation><intestinal epithelium><loss of function><mouse model><murine model><new drug target><new druggable target><new pharmacotherapy target><new therapeutic target><new therapy target><novel drug target><novel druggable target><novel pharmacotherapy target><novel therapeutic target><novel therapy target><pathway><pharmacologic><progenitor><protein blotting><research and development><resistant><response><social role><spatiotemporal><stem><therapeutic target><tool><transcriptomics>