Epigenetic regulation in therapeutic human pancreatic beta cell proliferation

治疗性人胰腺β细胞增殖的表观遗传调控

• 批准号: 10192020
• 负责人: Esra Karakose
• 金额: $ 15.29万
• 依托单位: ICAHN SCHOOL OF MEDICINE AT MOUNT SINAI
• 依托单位国家: 美国
• 财政年份: 2021
• 资助国家: 美国
• 起止时间: 2021-04-01 至 2024-12-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10192020
• 关键词: 3-Dimensional; ATAC-seq; Academia; Affect; Agonist; Architecture; Beta Cell; Biochemistry; Bioinformatics; Biological Assay; Blindness; Cell Proliferation; Cells; Cellular biology; Cessation of life; ChIP-seq; Characteristics; Chromatin; Chromatin Structure; Chronic; Chronic Disease; Data; Data Analyses; Development Plans; Diabetes Mellitus; Dialysis procedure; Disease; Doctor of Philosophy; Drug Targeting; Environment; Epigenetic Process; Faculty; Future; GCG gene; Genes; Genetic; Germany; Goals; Graph; High-Throughput Nucleotide Sequencing; Histones; Human; Hypertension; Immune; Impaired fasting glycaemia; Institutes; Insulin; Insulin-Dependent Diabetes Mellitus; Islets of Langerhans Transplantation; Kidney Failure; Leadership; Left; Light; Massive Parallel Sequencing; Measures; Mediating; Meleagris gallopavo; Mentors; Metabolic Diseases; Metabolism; Molecular; Molecular Biology; Molecular Genetics; Myocardial Infarction; Natural regeneration; Non-Insulin-Dependent Diabetes Mellitus; Obesity; Organ Donor; Pancreas; Pancreas Transplantation; Pathway interactions; Pattern; Pharmaceutical Preparations; Pharmacology; Pharmacotherapy; Population; Program Development; Proliferating; Property; Reporting; Research; Research Personnel; Residual state; Risk Factors; Role; Scientist; Stroke; Structure of beta Cell of islet; Technology; Therapeutic; Training; Transforming Growth Factor beta; Transplantation; Universities; Work; Writing; base; career; career development; cell regeneration; chromatin immunoprecipitation; chromosome conformation capture; cost; diabetes mellitus therapy; drug development; epigenetic regulation; experience; experimental study; inhibitor/antagonist; instructor; islet; medical schools; member; molecular sequence database; new therapeutic target; next generation sequencing; non-diabetic; novel; novel therapeutic intervention; novel therapeutics; premature; receptor; regenerative; regenerative cell; response; single-cell RNA sequencing; skills; stem cells; targeted treatment; transcriptome

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.

项目摘要 这是Esra Karakose博士的K-01申请表。她的首要目标是发现新的治疗方法 糖尿病的治疗方法该建议调查了表观遗传学在控制人类β细胞中的作用， 复制，旨在确定新的途径和药物靶点，使人类β细胞再生。 候选人Karakose博士是糖尿病肥胖和代谢研究所的初级教员（讲师） 在西奈山伊坎医学院她拥有土耳其Bilkent大学的理学硕士学位， 博士学位，著名的马克斯普朗克生物化学研究所，德国。她的丰富经验， 分子生物学和遗传学以及她在博士后期间在β细胞生物学方面的专业知识 她的工作使她做好了准备，成功地实现了这项建议的目标。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帮助她过渡到独立研究 职业：1）获得高级编程技能，以更好地分析和解释数据; 2）获得动手能力 具有单细胞RNA-seq实验和数据分析经验; 3）开发染色质构象捕获 实验和应用生物信息学分析;和，4）发展写作和领导能力。 导师/环境。Karakose博士将由她的主要导师Andrew Stewart博士指导， 其他非常有成就的科学家。马丁沃尔什博士是遗传学领域的杰出科学家， Sebra博士是下一代测序技术和分析的先驱。 西奈山提供最先进的实验室设施以及高度动态的科学环境，从而 为Karakose博士作为一名研究人员创造了一个很好的机会。 Research.目前逆转糖尿病中β细胞丢失的方法是有限的：胰岛移植，整体 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，包括器官捐献者数量不足，免疫排斥，缺乏 成功实施基于干细胞的策略的可能性，以及过高的成本。一个有前途 替代疗法是β细胞再生药物疗法。这一提议将是理解 目前的β细胞再生药物的作用，所有这些都通过涉及β细胞的机制发挥作用， 表观遗传学此外，它将为确定新的β细胞药物靶点提供重要信息 增殖目的1将确定人胰腺癌细胞中开放的染色质区域和组蛋白标记物 用再生药物治疗的β细胞目的2将确定增殖β细胞的表观遗传特性 单细胞方法。更具体地说，目标2a将定义人类基因组亚组的转录组。 具有增殖能力的胰腺β细胞群，而Aim 2b将定义3D染色质 在增殖的人类胰腺β细胞中的结构。