Insights into pancreatic beta-cell development from a novel mouse model of neonatal diabetes

项目总结

PROJECT SUMMARY Diabetes, a major cause of mortality and morbidity globally, has both polygenic (e.g., type 1 and type 2) and monogenic (e.g., neonatal diabetes mellitus (NDM)) causes. Identification of individual mutations underlying NDM has been instrumental in understanding pancreatic β-cell development and function in humans and for advancing precision medicine in diabetes. However, current diabetes treatments, including insulin therapy and oral medications, are not cures and do not remove the need for daily diabetes management. As such, there is a critical need for both improved diagnostics and targeted treatments for all forms of diabetes, including stem- cell replacements strategies, to improve patient quality of life and reduce secondary complications. This proposal will investigate the roles of a novel pancreatic development gene (Gins4) in the pathogenesis of monogenic (NDM) and type 2 diabetes in mice and humans. The Research Training Plan will leverage mouse and human genetics, in vitro stem cell differentiation, transcriptomics, and epigenomics to examine the role of Gins4 in pancreatic development. This project is uniquely positioned to couple state-of-the-art methodologies in in vivo and in vitro islet biology, stem cell differentiation, and bioinformatics. In Aim 1, the applicant, Dr. Jennifer Ikle, will train with mentor Dr. Anna Gloyn in in vitro stem cell models, gene editing techniques, and transcriptomic analyses of developing endocrine cells. In Aim 2, Dr. Ikle will train in protein-protein interactions and epigenomics by looking directly at both the protein and DNA interactions between Gins4 and its bindings partners. In Aim 3, Dr. Ikle will train in human genetics and translational research by assessing the potential for a role of GINS4 in both human neonatal and type 2 diabetes pathogenesis. Dr. Ikle has suitable prior training in embryonic development, genetics, and islet biology, with multiple first-author publications and presentations. The Career Development Plan is tailored to enable Dr. Ikle to gain new experimental skills and concepts in stem cell biology, gene editing, transcriptomics and epigenomics, as well as career skills through practice and coursework. Mentor Dr. Anna Gloyn is a leading expert in diabetes genetics, functional genomics, and islet-cell biology. Co-mentor Dr. Seung Kim (pancreatic islet development) and advisors Dr. Louis Philipson (monogenic diabetes), Dr. Lori Sussel (pancreatic embryology), and Dr. Julie Sneddon (pancreatic stem cell biology). The Environment at Stanford, including the NIH supported Stanford Diabetes Research Center (director: Dr. Seung Kim) and the Maternal and Child Health Research Institute, is an outstanding setting for collaborative and innovative research. World-class core facilities are available in the heart of vibrant silicon valley. In summary, the strong mentoring, environment, and training plan are anticipated to fully prepare Dr. Ikle to launch her independent career in diabetes genetics. The proposed studies promise to offer mechanistic insights into embryonic development of pancreatic islets which has the potential to provide opportunities to both improve precision medicine and in vitro stem-cell protocols for human beta-cell development.