Intestinal chondroitin sulfate glycosaminoglycans and their role in inflammatory bowel disease - PROJECT SUMMARY: This proposal details a 5-year program to provide training toward the development of an independent academic research career in the study of the extracellular matrix in inflammatory bowel disease (IBD). The candidate has prepared for this pathway by completing her MD and clinical training in Pediatrics with further specialization in Pediatric Gastroenterology. She has been scientifically productive in her early career, (four first-author manuscripts and a book chapter) and was awarded an NIH F32 Award in addition to the 2021 Fellow Research Award by the North American Society for Pediatric Gastroenterology, Hepatology, and Nutrition. The proposed research will be conducted in the laboratories of Dr. Michael Schwartz, a senior professor who has been nationally recognized for his mentorship, Dr. Jarrad Scarlett, a distinguished physician-scientist who is also a practicing gastroenterologist, and Dr. Kimberly Alonge, an expert in matrix biology. The applicant has assembled an Advisory Committee that includes an expert in mucosal immunology and translational IBD research (Dr. Edwin deZoeten), clinical experts in IBD (Dr. David Suskind and Dr. Betty Zheng), and a senior clinical researcher (Dr. Ellen Schur). She also has support from the University of Washington (UW) Mass Spectrometry Center and the UW Microbial Interactions and Microbiome Center. The proposal focuses on the applicant’s recent published work characterizing the chondroitin sulfate (CS) glycosaminoglycan (GAG) composition of the human intestine for the first time, showing pathologic changes associated with active IBD. Although the abundance of pro-inflammatory CS-GAG components correlates with clinical disease activity, whether modifications in the CS-GAG composition are integral to IBD pathogenesis and disease progression remains unanswered. Studies outlined in this proposal seek to determine whether the intestinal CS-GAG composition can serve as a therapeutic agent and disease biomarker in IBD. Aim 1 will use preclinical models of IBD to test the hypothesis that administering stabilizing CS-GAG elements improves IBD outcomes. Aim 2 will interrogate the role of CS-GAG composition as a clinical predictor tool and investigate whether the CS-GAG composition in intestinal biopsies from diagnosis can predict long-term clinical outcomes in patients with IBD and determine risk of colectomy in patients with acute severe colitis. The applicant’s combination of clinical expertise in IBD, knowledge of matrix biology, familiarity with mass spectrometry techniques, and prior published work using animal models of IBD, as well as her ability to directly translate her technical work to answer important clinical questions in her field of practice uniquely qualify her to conduct the studies in this proposal. The hypothesis that CS-GAGs play a crucial role in IBD pathogenesis and disease progression and have potential as a therapeutic target and clinical predictor is entirely novel and has the potential to dramatically impact the care of patients with IBD and will launch the candidate’s independent academic career.
