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: 10532768
• 负责人: Esra Karakose
• 金额: $ 15.14万
• 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/10532768
• 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; Databases; Development Plans; Diabetes Mellitus; Dialysis procedure; Disease; Doctor of Philosophy; Drug Combinations; 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; Insulin; Insulin-Dependent Diabetes Mellitus; Islets of Langerhans Transplantation; Kidney Failure; Leadership; Left; 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; Persons; Pharmaceutical Preparations; Pharmacology; Pharmacotherapy; Population; Postdoctoral Fellow; Program Description; 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; career; career development; cell regeneration; chromatin immunoprecipitation; chromosome conformation capture; cost; diabetes mellitus therapy; drug development; epigenetic regulation; experience; experimental analysis; experimental study; inhibitor; inhibitor therapy; instructor; islet; medical schools; member; 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应用程序。她的总体目标是发现新颖的治疗性 糖尿病的方法。该提案调查了表观遗传学在人类β细胞控制中的作用 复制，旨在识别将实现人β细胞再生的新型途径和药物靶标。 候选人。 Karakose博士是糖尿病肥胖和代谢研究所的初级教师（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硕士学位 德国著名的麦克斯·普朗克生物化学研究所获得博士学位。她在 分子生物学和遗传学以及她在博士后在Beta细胞生物学中发展的专业知识 工作使她准备成功实现该提案的目标。她的职业发展计划 包括四个培训目标，这将有助于她过渡到独立研究 职业：1）获得高级编程技能以更好地分析和解释数据； 2）亲身实践 具有单细胞RNA-seq实验和数据分析的经验； 3）发展染色质构象捕获 实验并应用生物信息学分析；以及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安德鲁·斯图尔特（Andrew Stewart）和两个 其他非常成就和免费的科学家。马丁·沃尔什（Martin Walsh）博士是遗传学的杰出科学家， 表观遗传学和药理学，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 为Karakose博士创造了一个绝佳的机会，成为研究人员。 研究。当前逆转糖尿病中β细胞损失的方法有限：胰岛移植，整个 胰腺移植和基于干细胞的可移植β细胞策略。但是，许多障碍 与这些方法有关，包括不足的器官捐献者，免疫排斥，缺乏 在基于干细胞的策略的情况下，成功实施的实施和成本过高。有希望的 替代性是β细胞再生药物疗法。该建议将是了解机制的关键 当前β细胞再生药物的作用，所有这些药物都通过涉及β细胞的机制起作用 表观遗传学。此外，它将提供至关重要的信息，以识别β细胞的新药物目标 增殖。 AIM 1将定义人类胰腺中的开放染色质区域和组蛋白标记签名 用再生药物处理的β细胞。 AIM 2将确定增殖β细胞的表观遗传特性 使用单细胞方法。更具体地说，AIM 2A将定义人类子集的转录组 胰腺β细胞群具有增殖能力，而AIM 2B将定义3D染色质 增殖人胰腺β细胞的结构。