Project Grant F32DK139701

LEVERAGING THE GASTRIC SUBMUCOSA AS A HOST FOR CELL THERAPIES - THE OBJECTIVE OF THESE STUDIES IS TO BETTER UNDERSTAND SUBMUCOSAL BIOLOGY AS IT RELATES TO IMPLANTATION OF CELL THERAPY DEVICES. ENDOSCOPIC SUBMUCOSAL DISSECTION (ESD) IS EMPLOYED TO ACCESS THE GASTROINTESTINAL (GI) SUBMUCOSA FOR EXCISION OF LESIONS, THERAPEUTIC MYOTOMY, AND EVEN PERITONEAL ACCESS. EXPANSION OF THIS TECHNIQUE TO INCLUDE DEVICE IMPLANTATION COULD ENABLE NOVEL APPROACHES TO LONG-TERM DELIVERY OF THERAPEUTICS, INCLUDING CELL THERAPIES, TO THE GI TRACT. HOWEVER, THE BIOLOGY OF THE SUBMUCOSAL SPACE AS A HOST FOR IMPLANTABLE DEVICES IS NOT WELL UNDERSTOOD. THE LONG-TERM GOAL IS TO LEVERAGE THE GI SUBMUCOSA AS A HOST FOR REGENERATIVE THERAPIES IN THE TREATMENT OF DEGENERATIVE OR AUTOIMMUNE GI PATHOLOGIES. THE CENTRAL HYPOTHESIS OF THE PROPOSED WORK IS THAT THE SUBMUCOSA CAN SERVE AS AN EFFECTIVE HOST FOR CELL THERAPIES. A MODEL INVOLVING PANCREATIC ISLET TRANSPLANTATION INTO THE GASTRIC SUBMUCOSA FOR THE TREATMENT OF TYPE 1 DIABETES (T1D) WILL BE EMPLOYED, INSPIRED BY THE FINDING OF SUBEPITHELIAL HETEROTOPIC PANCREATIC TISSUE (OR "PANCREATIC RESTS") INCIDENTALLY FOUND ON BIOPSIES OF THE STOMACH. THE PANCREATIC ISLET IS A COMPELLING CELL MODEL AS THERE ARE EXISTING ANIMAL MODELS FOR T1D AND VALIDATED ASSAYS TO QUANTIFY ISLET SURVIVAL AND FUNCTION. THE RATIONALE IS THAT EVALUATION OF THE GASTRIC SUBMUCOSA AS A POTENTIAL HOST FOR CELL THERAPIES MAY NOT ONLY LEAD TO BREAKTHROUGHS IN THE TREATMENT OF T1D, BUT ALSO LOCALIZED TREATMENT OF DEGENERATIVE GI DISORDERS IN WHICH NORMAL TISSUE HAS BEEN COMPROMISED. THE CENTRAL HYPOTHESIS WILL BE TESTED BY PURSUING 3 SPECIFIC AIMS: 1) EVALUATE ENDOSCOPIC PROCEDURE TECHNIQUE AND SAFETY FOR SUBMUCOSAL IMPLANTATION IN A SWINE MODEL; 2) CHARACTERIZE IN VIVO HOST RESPONSE TO SUBMUCOSALLY IMPLANTED MATERIALS AND DEVICES; AND 3) DETERMINE ENCAPSULATED ISLET SURVIVAL AND FUNCTION AS WELL AS PHENOTYPIC RESCUE. FOR AIM 1, A SWINE MODEL WILL BE USED TO EVALUATE OUTCOMES AND COMPLICATIONS OF ESD WITH AND WITHOUT DEVICE IMPLANTATION, USING DEVICES OF VARIOUS GEOMETRIES. TO ACHIEVE AIM 2, TISSUE HISTOLOGY, IMMUNOFLUORESCENT STAINING, FLOW CYTOMETRY, RT-PCR, AND SCRNA-SEQ WILL BE USED TO EVALUATE THE HOST RESPONSE TO ESD/DEVICE IMPLANTATION AS COMPARED TO THE MORE COMMON METHODS OF SUBCUTANEOUS AND INTRAPERITONEAL IMPLANTATION. FOR AIM 3, DEVICES CONTAINING A TEST DOSE OF ALLOGENEIC ISLETS WILL BE IMPLANTED INTO THE GASTRIC SUBMUCOSA TO EVALUATE ISLET SURVIVAL AND FUNCTION (USING IMMUNOFLUORESCENT STAINING, RT-PCR, AND SCRNA-SEQ), AND IF SUCCESSFUL, THERAPEUTIC DOSES WILL BE IMPLANTED IN A T1D SWINE MODEL TO EVALUATE FOR PHENOTYPIC RESCUE. THE PROPOSED RESEARCH IS SIGNIFICANT AS IT WILL DEMONSTRATE A NOVEL APPROACH TO GI DEVICE DELIVERY AND IMPROVE UNDERSTANDING OF SUBMUCOSAL BIOLOGY AS IT PERTAINS TO DEVICE IMPLANTATION. ULTIMATELY, THIS WILL CONTRIBUTE NOT ONLY TO THE FIELD OF T1D AND CELL THERAPIES, BUT ALSO OFFER VALUABLE INSIGHTS FOR THE FUTURE DEVELOPMENT OF SUBMUCOSALLY IMPLANTED LOCALIZED TREATMENT OF OTHER DISORDERS, INCLUDING DEGENERATIVE GI DISORDERS. THIS PROJECT WILL PROVIDE UNPARALLELED TRAINING EXPERIENCE TO THE APPLICANT IN THE TRANSLATIONAL ASPECTS OF IMPLANTABLE DEVICE DESIGN, LARGE ANIMAL MODELS, AND SUBMUCOSAL BIOLOGY.