Epigenetic regulation in therapeutic human pancreatic beta cell proliferation

项目摘要 这是针对Esra Karakose博士的K-01申请。她的首要目标是发现新的治疗方法 糖尿病的治疗方法。这项建议调查了表观遗传学在人类β细胞控制中的作用。 复制，旨在确定能够使人类β细胞再生的新途径和药物靶点。 候选人。卡拉科斯博士是糖尿病肥胖和代谢研究所的初级教员(讲师) 在西奈山的伊坎医学院。她拥有土耳其比尔肯特大学的理学硕士学位，并拥有 德国著名的马克斯·普朗克生物化学研究所博士学位。她在以下领域的丰富经验 分子生物学和遗传学，以及她在博士后期间积累的β细胞生物学专业知识 工作使她做好了准备，能够成功地实现这项提案的目标。她的职业发展计划 包括四个培训目标，所有这些都将有助于她过渡到独立研究 职业生涯：1)掌握高级编程技能，以便更好地分析和解释数据；2)实践经验 具有单细胞rna-seq实验和数据分析经验；3)发展染色质构象捕捉。 实验和应用生物信息学分析；以及，4)发展写作和领导技能。 导师/环境。卡拉科斯博士将由她的主要导师安德鲁·斯图尔特博士和两名 更多非常有成就的和受人称赞的科学家。马丁·沃尔什博士是一位杰出的遗传学科学家， 塞布拉博士是下一代测序技术和分析的先驱。 西奈山提供了最先进的实验室设施和高度动态的科学环境，从而 这为卡拉科斯博士成为一名研究人员创造了一个极好的机会。 研究。目前逆转糖尿病患者β细胞丢失的方法有限：胰岛移植 胰腺移植和基于干细胞的可移植β细胞策略。然而，许多障碍 与这些方法有关，包括器官捐赠者数量不足，免疫排斥，缺乏 在以干细胞为基础的战略的情况下，成功实施的可能性很大，而且成本过高。一个有希望的人 可供选择的是贝塔细胞再生药物疗法。这一提议将是理解 当前的β细胞再生药物的作用，所有这些药物都通过涉及β细胞的机制发挥作用 表观遗传学。此外，它还将为确定β细胞的新药物靶点提供关键信息。 扩散。目标1将确定人胰腺的开放染色质区域和组蛋白标记信号 用再生药物治疗的β细胞。AIM 2将确定增殖的β细胞的表观遗传学特性 用单细胞方法。更具体地说，目标2a将定义人类子集的转录 具有增殖能力的胰岛β细胞群，而Aim 2b将定义3D染色质 增殖的人胰岛β细胞的结构。

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.