Project Grant F30DE036430

SYSTEMIC BILE ACID DYSREGULATION DRIVES ALVEOLAR BONE LOSS IN COLITIS - PROJECT SUMMARY/ABSTRACT COLITIS IS A CHRONIC INFLAMMATORY GUT DISORDER WITH SIGNIFICANT EXTRAINTESTINAL MANIFESTATIONS. THESE INCLUDE A HIGH PREVALENCE OF PERIODONTITIS, A DISEASE DEFINED BY SUBSTANTIAL ALVEOLAR BONE LOSS. THE MECHANISM LINKING INTESTINAL INFLAMMATION TO ORAL BONE PATHOLOGY REMAINS A CRITICAL KNOWLEDGE GAP. THIS F30 APPLICATION WILL INVESTIGATE A NOVEL GUT-METABOLITE-ORAL BONE AXIS. THE CENTRAL HYPOTHESIS IS THAT COLITIS-INDUCED GUT DYSBIOSIS ALTERS THE SYSTEMIC BILE ACID PROFILE, INCREASING THE RATIO OF PRIMARY TO SECONDARY BILE ACIDS, WHICH IN TURN DRIVES ALVEOLAR BONE LOSS BY INHIBITING THE PRO-OSTEOGENIC NUCLEAR FARNESOID X RECEPTOR (FXR) IN BONE CELLS. THE RESEARCH PLAN WILL TEST THIS HYPOTHESIS THROUGH THREE SPECIFIC AIMS. AIM 1 WILL USE A DEXTRAN SULFATE SODIUM (DSS) MOUSE MODEL OF COLITIS TO DEMONSTRATE THAT INTESTINAL INFLAMMATION INDUCES SYSTEMIC BILE ACID DYSREGULATION AND PROMOTES ALVEOLAR BONE LOSS. AIM 2 WILL DEFINE THE DIRECT EFFECTS OF A COLITIS-ASSOCIATED BILE ACID COCKTAIL ON THE FUNCTION OF PRIMARY OSTEOBLASTS AND OSTEOCLASTS IN VITRO USING FUNCTIONAL ASSAYS. AIM 3 WILL DETERMINE IF THE PATHOGENIC BILE ACID PROFILE PHENOCOPIES GENETIC FXR DELETION IN OSTEOBLAST- AND OSTEOCLAST-LINEAGE CELLS, USING IN VITRO INDUCIBLE CRE-LOX MOUSE MODELS. THE FELLOWSHIP APPLICATION WILL SUPPORT A D.M.D./PH.D. CANDIDATE WHOSE LONG-TERM GOAL IS TO BECOME AN INDEPENDENT ACADEMIC ORTHODONTIST-SCIENTIST. THE CANDIDATE'S TRAINING PLAN, DEVELOPED WITH SPONSORS DR. WESTWATER (HOST-MICROBE INTERACTIONS) AND DR. ENGEVIK (DIGESTIVE DISEASES), WILL STRENGTHEN THE APPLICANT'S SCIENTIFIC EXPERTISE, LEADERSHIP AND MENTORING SKILLS, AND INTERDISCIPLINARY PROFESSIONAL NETWORK. TECHNICAL TRAINING WILL INCLUDE ADVANCED CRANIOFACIAL HISTOMORPHOMETRY, IN VITRO BONE CELL FUNCTIONAL ASSAYS, LC- MS/MS METABOLOMICS, AND BIOINFORMATIC INTEGRATION OF MULTI-OMICS DATASETS. A CORE COMPONENT OF THE TRAINING PLAN IS THE INTENTIONAL INTEGRATION OF SCIENTIFIC AND CLINICAL COMPETENCE IN BASIC SCIENCE RESEARCH AND DENTISTRY. TRAINING WILL OCCUR WITHIN THE SUPPORTIVE ENVIRONMENT OF THE MEDICAL UNIVERSITY OF SOUTH CAROLINA, LEVERAGING THE NIDDK-FUNDED DIGESTIVE DISEASES RESEARCH CORE CENTER (DDRCC) AND THE NIDCR-FUNDED TRAINING IN CRANIOFACIAL AND ORAL HEALTH RESEARCH (T-COHR). THIS PROJECT WILL PROVIDE FUNDAMENTAL INSIGHTS INTO GUT-SKELETAL CROSSTALK AND PREPARE THE CANDIDATE FOR A TRANSLATIONAL RESEARCH CAREER AS A DENTIST-SCIENTIST.