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

项目总结 糖尿病是全球死亡率和发病率的主要原因，它既有多基因(如1型和2型)，也有 单基因(例如，新生儿糖尿病(NDM))原因。鉴定潜在的个体突变 NDM有助于了解人类胰腺β细胞的发育和功能 推进糖尿病的精准医学。然而，目前的糖尿病治疗，包括胰岛素治疗和 口服药物不是治愈糖尿病的方法，也不会消除日常糖尿病管理的需要。因此，有 迫切需要改善所有形式的糖尿病的诊断和有针对性的治疗，包括干细胞- 细胞替代策略，以提高患者的生活质量，减少继发性并发症。这 一项提案将研究一种新的胰腺发育基因(Gins4)在糖尿病发病机制中的作用 小鼠和人类的单基因(NDM)和2型糖尿病。研究培训计划将利用MICE 以及人类遗传学、体外干细胞分化、转录组学和表观基因组学的作用 Gins4在胰腺发育中的作用这个项目的独特之处在于结合了最先进的方法 在体内和体外的胰岛生物学、干细胞分化和生物信息学。在目标1中，申请者Dr。 Jennifer Ikle将与导师Anna Gloyn博士一起在体外干细胞模型、基因编辑技术和 发育中的内分泌细胞的转录切分分析。在目标2中，伊克尔博士将接受蛋白质-蛋白质相互作用方面的培训 和表观基因组学，通过直接研究Gins4与其结合之间的蛋白质和DNA相互作用 合伙人。在目标3中，伊克尔博士将通过评估人类遗传学和翻译研究的潜力来培训 GINS4在新生儿和2型糖尿病发病机制中的作用。伊克尔博士曾接受过适当的培训 胚胎发育、遗传学和胰岛生物学，有多个第一作者的出版物和演讲。 职业发展计划旨在帮助伊克尔博士在以下领域获得新的实验技能和概念 干细胞生物学、基因编辑、转录学和表观基因组学，以及通过实践和 课程作业。导师Anna Gloyn博士是糖尿病遗传学、功能基因组学和胰岛细胞方面的领先专家 生物学。共同导师Seung Kim博士(胰岛发育)和顾问Louis Philipson博士(单基因 Lori Sussel博士(胰腺胚胎学)和Julie Sneddon博士(胰腺干细胞生物学)。这个 斯坦福大学的环境，包括NIH支持的斯坦福糖尿病研究中心(主任：Seung博士 Kim)和妇幼保健研究所，是合作和 创新研究。在充满活力的硅谷中心，有世界级的核心设施。总而言之， 强大的指导、环境和培训计划预计将使伊克尔博士为启动她做好充分的准备 独立从事糖尿病遗传学研究。拟议中的研究承诺提供对 胰岛的胚胎发育，有可能为两者提供改善的机会 用于人类β细胞发育的精确医学和体外干细胞方案。

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.