Document text
Principal Investigator: Nan Gao
Organization: RUTGERS BIOMEDICAL AND HEALTH SCIENCES
Fiscal Year: 2024
Award: $427,257
Funding agency: National Institute of Diabetes and Digestive and Kidney Diseases
PROJECT SUMMARY
Crohn’s disease (CD) is a form of IBD that commonly involves small intestine, where the majority of Paneth cells
reside. As a great number of CD patients show no response or refractory to standard treatment, there is an
unmet need for new therapeutic options based on new mechanisms of action. Recent studies suggested that
defective Paneth cells may play the key role in initiating inflammation in ileal, and maybe ileocecal CD. Paneth
cells in CD patients or mouse IBD models often exhibit granule phenotypes characterized initially by Dr. Ta-
Chiang Liu, where several Paneth cell-enriched antimicrobial factors, instead of being packed into secretory
granules, are dispersed to the cytoplasm. Hypotheses relating to defective ER stress, autophagy, and secretion
have been developed to interpret these CD Paneth cell defects, however the cause-and-effect relationship
remains obscure. To date, existing studies has been treating Paneth cells as a homogeneous population. Based
on a newly developed temporally controlled Paneth cell reporter mouse model, we establish single cell
transcriptomic maps for ileal Paneth cells in homeostasis, dysbiosis, infection and inflammation conditions. We
found that there is a profound change in Paneth cell heterogeneity in response to microbiota alteration, infection,
and potentially genetic risk factors. Analyzing Paneth cell populations across different conditions revealed an
immunologically activated Paneth cell subset that has distinct antimicrobial peptide profile, enriched cytokine
receptor, and heightened innate immune and degranulation activities. Paneth cells carrying the signature
markers are found in ileal CD and UC metaplastic lesions. We will test the hypothesis that a dynamic Paneth cell
heterogeneity regulated by interactions of genetic, gut microbiota, and environmental factors such as pathogen
infection is critical for activation of Paneth cell-mediated innate protection against inflammatory induction and
aggravation. Aim 1 will determine the function and disease relevance of these Paneth cells by examine their
innate immune function, degranulation capacity, chromatin and epigenetic profile, in vivo role of specifically
secreted mucosal pentraxins, and relevance to CD Paneth cell defects and clinical outcomes. Aim 2 will test how
two Paneth cell intrinsic pathways and CD dysbiotic microbiota affect Paneth cell heterogeneity, by performing
Paneth cell specific genetic ablation and overexpression, as well as fecal microbiome transplantation in newly
developed germ-free Paneth cell reporter mice. This proposal addresses a significant and innovative hypothesis
relating to Paneth cell heterogeneity that may contribute to the causality and mechanism of Paneth cell-driven
CD pathogenesis. Once a new mechanism regulating proper Paneth cell activation and inflammatory protection
is identified, it may be leveraged for IBD intervention.
Terms: <Ablation><Address><Affect><Autophagocytosis><Autoregulation><Body Tissues><Causality><Cell Body><Cells><Chromatin><Clinical><Crohn disease><Crohn's><Crohn's disease><Crohn's disorder><Cytokine Receptors><Cytoplasm><Cytoplasmic Granules><Data><Defect><Diathesis><Diffusion><Disease><Disease remission><Disease susceptibility><Disorder><ER stress><Environmental Factor><Environmental Risk Factor><Epigenetic><Epigenetic Change><Epigenetic Mechanism><Epigenetic Process><Etiology><Exhibits><Experimental Designs><Expression Signature><GEM model><GEMM model><GI microbiota><Gastrointestinal microbiota><Gene Expression Profile><Genetic><Genetic Risk><Genetic predisposing factor><Genetically Engineered Mouse><Germ-Free><Gnotobiotic><Gnotobiotics><Granulomatous Enteritis><Heterogeneity><Homeostasis><Human><Immune><Immune response><Immunes><Immunochemical Immunologic><Immunologic><Immunological><Immunological response><Immunologically><Immunologics><Impairment><Infection><Inflammation><Inflammatory><Inflammatory Bowel Diseases><Inflammatory Bowel Disorder><Injury><Innate Immune Response><Intervention><Intervention Strategies><Intestinal><Intestines><Investigators><Label><Lesion><Link><Maps><Mediating><Mice><Mice Mammals><Modeling><Modern Man><Molecular><Mucosa><Mucosal Tissue><Mucous Membrane><Murine><Mus><Onset of illness><Outcome><Paneth Cells><Pathogenesis><Pathology><Pathway interactions><Patients><Phenotype><Physiological Homeostasis><Play><Population><Production><Recurrence><Recurrent><Refractory><Relapse><Remission><Reporter><Reporting><Research Personnel><Researchers><Role><Secretory Granules><Secretory Vesicles><Severities><Small Intestines><Testing><Tissues><UTRs><Ulcerated Colitis><Ulcerative Colitis><Untranslated Regions><anti-microbial><anti-microbial peptide><antimicrobial><autophagy><bowel><bowel inflammation><causation><design><designing><diffused><diffuses><diffusing><diffusions><disease causation><disease model><disease onset><disorder model><disorder onset><dysbacteriosis><dysbiosis><dysbiotic><eleocolitis><endoplasmic reticulum stress><enteric microbial community><enteric microbiota><environmental risk><epigenetically><experiment><experimental research><experimental study><experiments><fecal microbial transplantation><fecal microbiome transplantation><fecal microbiota transplant><fecal microbiota transplantation><fecal transplant><fecal transplantation><gastrointestinal microbial flora><gene expression pattern><gene expression signature><genetic risk factor><genetically engineered mouse model><genetically engineered murine model><granule><gut commensal><gut community><gut flora><gut inflammation><gut microbe community><gut microbial community><gut microbial composition><gut microbial consortia><gut microbiota><gut microbiotic><gut microflora><host response><immune system response><immunoresponse><in vivo><inflamed bowel><inflamed gut><inflamed intestine><inflammatory disease of the intestine><inflammatory disorder of the intestine><inherited factor><injuries><innate immune function><innate immune sensing><innovate><innovation><innovative><interventional strategy><intestinal autoinflammation><intestinal flora><intestinal inflammation><intestinal microbiota><intestinal microflora><intestinal tract microflora><liability to disease><microbial consortia><microbial flora><microbial imbalance><microbiome><microbiome transplant><microbiome transplantation><microbiota><microbiota transplant><microbiota transplantation><microflora><mouse model><multispecies consortia><murine model><new drug treatments><new drugs><new pharmacological therapeutic><new therapeutics><new therapy><next generation therapeutics><novel drug treatments><novel drugs><novel pharmaco-therapeutic><novel pharmacological therapeutic><novel therapeutics><novel therapy><overexpress><overexpression><pathogen><pathway><regional enteritis><response><response to therapy><response to treatment><small bowel><social role><standard care><standard of care><standard treatment><therapeutic response><therapy response><transcriptional profile><transcriptional signature><transcriptomics><treatment response><treatment responsiveness>