The Role of SOX2 and CDX2 in Barrett's Esophagus Development

PROJECT SUMMARY / ABSTRACT This K08 application proposes a five-year career development and research program focused on elucidat- ing the transcriptional determinants and molecular heterogeneity of Barrett’s esophagus (BE). The applicant, Ramon Jin, M.D., Ph.D., is a physician-scientist and an Instructor in Medicine in the Section of Hematology and Oncology, Department of Medicine, at Baylor College of Medicine (BCM). Since completing his hematology and oncology fellowship as a chief fellow, Dr. Jin has worked in the laboratory of Dr. Jason Mills, where he has applied his foundation in molecular cell biology to study Barrett’s esophagus and upper gastrointestinal (GI) metaplasias through development of genetic mouse models and establishment of human patient-derived organoids. From a GI developmental perspective, Barrett’s metaplasia reflects a “caudalization” process with loss of esophageal and gain in both gastric and intestinal traits. Specifically, two pioneering transcription factors involved in GI tract patterning, SOX2 and CDX2, are likely to involved, and the proposed research is based on the hypothesis that SOX2 decrease and CDX2 gain are critical steps during BE development and maintenance. To address this hypothesis, Dr. Jin proposes to carry out two specific aims: 1) Characterize the effects of SOX2 and CDX2 dis- ruption on foregut homeostasis with and without bile acid treatment, and 2) Determine the effects of SOX2 and CDX2 restoration on BE maintenance and the molecular heterogeneity of BE. Continued mentorship and protected research time provided by this grant will ensure the support needed to complete these aims and allow Dr. Jin sufficient time to establish an independent research program. Specif- ically, the current award would provide an important opportunity to train in multi-omics techniques and bioinfor- matic analyses, while expanding a unique set of tools including genetically modified mouse models and human BE and gastroesophageal cancer organoids. Dr. Jin’s career development will be nurtured through continued mentorship by Dr. Jason Mills and his mentorship committee. Drs. Cristian Ciorfa and Bing Zhang are both es- tablished computational scientists specializing in bioinformatic integration of multi-omic data; Dr. Kunal Rai is an expert in epigenomic regulation of development and oncogenesis; and Dr. Sarah Blutt is a leader in advanced GI organoid culturing techniques. Dr. Jin’s career development will be supplemented by continued growth in grant- manship, mentorship, leadership, and research community integration through courses and programs offered at BCM; involvement in ad hoc publication, abstract, and grant reviews; active participation in local and national research meetings; and preparation of manuscripts and grants. The guidance provided by his highly experienced research mentor and mentorship committee, the knowledge and technical skills derived from the proposed ex- periments, and the completion of the carefully outlined career development plan will allow Dr. Jin to successfully establish an independent research program that will be highly competitive for R01 funding.