Epigenetic regulation in therapeutic human pancreatic beta cell proliferation

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Project Summary This is a K-01 application for Esra Karakose, PhD. Her overarching goal is discovering novel therapeutic approaches for diabetes. This proposal investigates the role of epigenetics in the control of human beta cell replication, aiming to identify novel pathways and drug targets that will enable human beta cell regeneration. Candidate. Dr. Karakose is a junior faculty member (Instructor) at the Diabetes Obesity and Metabolism Institute at Icahn School of Medicine at Mount Sinai. She holds a M.Sc degree from Bilkent University, Turkey, and a Ph.D degree from the prestigious Max Planck Institute for Biochemistry, Germany. Her extensive experience in molecular biology and genetics as well as the expertise she developed in beta cell biology during her postdoctoral work have prepared her to successfully accomplish the objectives of this proposal. Her career development plan includes four training goals all which will be instrumental to help her transition into an independent research career: 1) Acquire advanced programming skills to better analyze and interpret data; 2) Gain hands-on experience in single cell RNA-seq experiments and data analysis; 3) Develop Chromatin Conformation Capture experiments and apply bioinformatics analysis; and, 4) Develop writing and leadership skills. Mentors/Environment. Dr. Karakose will be mentored by her primary mentor, Dr. Andrew Stewart, and two additional very accomplished and complimentary scientists. Dr. Martin Walsh is a prominent scientist in genetics, epigenetics and pharmacology, and Dr. Sebra is a pioneer in next-gen sequencing technologies and analysis. Mount Sinai provides state-of-the-art lab facilities as well as a highly dynamic scientific environment, thereby creating an excellent opportunity for Dr. Karakose to thrive as a researcher. Research. Current approaches to reverse beta cell loss in diabetes are limited: islet transplantation, whole pancreas transplantation and stem cell-based strategies for transplantable beta cells. However, many hurdles are associated with these approaches, including an insufficient number of organ donors, immune rejection, lack of successful implementation in the case of stem cell-based strategies, and excessive cost. A promising alternative is beta cell regenerative drug therapies. This proposal will be key to understand the mechanisms of actions of the current beta cell regenerative drugs, all of which work through mechanisms involving beta cell epigenetics. Moreover, it will provide crucial information for identifying novel drug targets for beta cell proliferation. Aim 1 will define the open chromatin regions and histone mark signatures in of human pancreatic beta cells treated with regenerative drugs. Aim 2 will determine epigenetic properties of proliferating beta cells with single cell approaches. More specifically, Aim 2a will define the transcriptomes of the subset of human pancreatic beta cell populations with the proliferative capacity, whereas Aim 2b will define 3D chromatin architecture in proliferating human pancreatic beta cells.