Project Grant R03DK140419

MECHANISMS OF OBESITY-RELATED ALTERED STOMACH PLASTICITY - PROJECT SUMMARY INDIVIDUALS WITH TYPE 2 DIABETES AND OBESITY ARE AT GREATER RISK FOR DEVELOPING GASTROINTESTINAL DISEASES INCLUDING CROHN'S DISEASE, GASTRO-ESOPHAGEAL REFLUX DISEASE, VARIOUS GASTROINTESTINAL CANCERS, AS WELL AS DIVERTICULOSIS. IN ORDER TO DEVELOP TREATMENTS TO REVERSE PATHOGENESIS, IT IS NECESSARY TO DETERMINE HOW CELLULAR CHANGES TO THE TISSUES OF THE GASTROINTESTINAL TRACT CONTRIBUTE TO DISEASE. INTERESTINGLY, THE EXPRESSION OF GENES IN THE STOMACH ARE MORE STRONGLY ALTERED COMPARED TO REGIONS OF THE SMALL AND LARGE INTESTINE DURING OBESITY. AND WHILE THE ABUNDANCE OF MANY GASTRIC CELLS, PARTICULARLY HORMONE-SECRETING ENDOCRINE CELLS, ARE INCREASED WITH DISEASE, THERE IS EVIDENCE TO SUPPORT THAT THESE CELLS ARE DYSFUNCTIONAL. THE MECHANISMS INITIATING THESE CHANGES REMAIN UNCLEAR. ENDOCRINE CELLS ARE REPOPULATED FROM STEM AND PROGENITOR CELLS. IN PRELIMINARY EVIDENCE PRESENTED IN THIS PROPOSAL, THE CANDIDATE HAS FOUND THAT THERE ARE MORE GASTRIC NEUROG3+ ENDOCRINE PROGENITOR CELLS, BUT MINIMAL CHANGE IN LGR5+ STEM CELLS, WITH DISEASE, THE LATTER OF WHICH IS DIFFERENT FROM WHAT IS FOUND IN THE INTESTINE. FURTHERMORE, THE CANDIDATE HAS FOUND A CELL-SPECIFIC INCREASE IN NOTCH COMPONENTS IN THE STOMACH OF MICE AFTER HIGH FAT DIET FEEDING. USING TWO SPECIFIC AIMS, THE GOAL OF THIS PROPOSAL IS TO DETERMINE HOW OBESITY ALTERS THE FUNCTION AND DISTRIBUTION OF GASTRIC ENDOCRINE PROGENITOR CELLS. THE HYPOTHESIS IS THAT LIPOTOXICITY DISRUPTS STEM AND PROGENITOR CELL HOMEOSTASIS THROUGH ALTERED NOTCH SIGNALING. IN AIM1, THROUGH GAIN-OF- FUNCTION STUDIES IN MICE, THE CANDIDATE WILL DIRECTLY TEST WHETHER ACTIVATION OF NOTCH SIGNALING CONTRIBUTES TO THE METABOLIC DYSREGULATION AND ALTERED FUNCTION OF GASTRIC ENDOCRINE CELLS THAT OCCURS DURING OBESITY. IN AIM2, USING FLUORESCENT REPORTER MICE TO MARK PROGENITOR AND LINEAGE-COMMITTED ENDOCRINE POPULATIONS, THE CANDIDATE WILL PERFORM SINGLE CELL RNA-SEQ TO ISOLATE UNIQUE POPULATIONS OF DYSFUNCTIONAL GASTRIC ENDOCRINE CELLS. IN ADDITION, USING A TARGETED APPROACH, THE CANDIDATE WILL ALSO DIRECTLY TEST, USING KNOCKOUT MICE, THE ROLE OF THE NOTCH LIGAND JAG1 IN PROMOTING THE EXPANSION OF ENDOCRINE CELLS WITH OBESITY. UPON COMPLETION, THE APPLICANT WILL HAVE CREATED A DETAILED PICTURE ON HOW UNIQUE POPULATIONS OF GASTRIC ENDOCRINE CELLS ARE ALTERED BY OBESITY. THE APPLICANT WILL ALSO ELUCIDATE HOW SPECIFIC SIGNALING MECHANISMS, SUCH AS ALTERED NOTCH SIGNALING, ARE CONNECTED TO DISEASE PATHOGENESIS. TOGETHER, THESE STUDIES WILL FORM THE BASIS OF AN R01 GRANT, ARE NECESSARY TO PERMIT A MORE COMPLETE ANALYSIS OF REGIONAL SPECIFIC DIFFERENCES IN ENDOCRINE CELL LINEAGE, AND WILL SHED LIGHT ON NEW THERAPEUTICS FOR DIABETES AND OBESITY.