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

从新生儿糖尿病的新型小鼠模型深入了解胰腺 β 细胞的发育

• 批准号: 10507398
• 负责人: Jennifer M Ikle
• 金额: $ 16.86万
• 依托单位: STANFORD UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2022
• 资助国家: 美国
• 起止时间: 2022-09-01 至 2023-07-05
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10507398
• 关键词: Affect; B Cell Proliferation; B-Cell Development; Beta Cell; Binding; Bioinformatics; Biology; Caring; Cell Count; Cell Proliferation; Cell model; Cells; Cellular Morphology; Cellular biology; Chicago; Collaborations; Complex; Computational Biology; Computer Analysis; Core Facility; DNA; DNA biosynthesis; Data; Data Set; Defect; Development; Development Plans; Diabetes Mellitus; Diagnosis; Diagnostic; Differentiated Gene; Embryo; Embryology; Embryonic Development; Endocrine; Environment; Failure to Thrive; Family; Fetal Development; Foundations; Future; Gene Expression; Generations; Genes; Genetic; Genetic Research; Genetic Transcription; Genome; Goals; Heart; Human; Human Genetics; Hyperglycemia; Hyperglycemic Mice; Impairment; In Vitro; Individual; Insulin; Insulin deficiency; International; Islet Cell; Islets of Langerhans; Knowledge; Lead; Maternal and Child Health; Mentors; Messenger RNA; Methodology; Morbidity - disease rate; Mus; Mutant Strains Mice; Mutation; Neonatal; Non-Insulin-Dependent Diabetes Mellitus; Oral; Pancreas; Pathogenesis; Pathology; Patients; Pharmaceutical Preparations; Phenotype; Play; Positioning Attribute; Precision therapeutics; Professional Competence; Protein Isoforms; Proteins; Protocols documentation; Publications; Quality of life; RNA Splicing; Research; Research Institute; Research Personnel; Research Training; Role; Silicon; Specificity; Structure; Structure of beta Cell of islet; Techniques; Time; Tissues; Training; Translational Research; United States National Institutes of Health; Universities; Untranslated RNA; Variant; beta cell replacement; career; career development; cell type; cost; diabetes management; diabetes mellitus genetics; diabetes pathogenesis; diabetes risk; directed differentiation; embryonic stem cell; endocrine pancreas development; epigenomics; functional genomics; genetic disorder diagnosis; genetic linkage analysis; genetic variant; genome sequencing; improved; in vivo; induced pluripotent stem cell; infancy; innovation; insight; islet; islet stem cells; maturity onset diabetes of the young; mortality; mouse genetics; mouse model; mutant; neonatal diabetes mellitus; neonatal human; novel; pancreas development; personalized medicine; precision medicine; progenitor; protein function; protein protein interaction; risk variant; skills; stem cell biology; stem cell differentiation; stem cell model; stem cell replacement; stem cells; success; transcriptomics; treatment planning; whole genome

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.

项目摘要 糖尿病是全球死亡率和发病率的主要原因，具有多基因（例如1型和2型）和 单基因（例如新生儿糖尿病（NDM））引起的。识别基础突变 NDM一直在了解胰腺β细胞的发展和功能 在糖尿病中推进精度医学。但是，当前的糖尿病治疗，包括胰岛素治疗和 口服药物，不是治愈的，也不会消除每日糖尿病管理的需求。因此，有 对所有形式的糖尿病的诊断和有针对性的治疗都需要改善的临界需求，包括STEM- 细胞替代策略，以提高患者的生活质量并减少继发性并发症。这 提案将研究一种新型胰腺发育基因（GINS4）在发病机理中的作用 小鼠和人类中的单基因（NDM）和2型糖尿病。研究培训计划将利用鼠标 和人类遗传学，体外干细胞分化，转录组学和表观基因组学检查的作用 胰腺发育中的GINS4。这个项目是唯一地定位于夫妇最先进的方法论 在AIM 1中，申请人博士 Jennifer Ikle，将与导师Anna Gloyn博士在体外干细胞模型，基因编辑技术和 发展内分泌细胞的转录组分析。在AIM 2中，Ikle博士将培训蛋白质 - 蛋白质相互作用 和表观基因组学通过直接查看Gins4及其结合之间的蛋白质和DNA相互作用 合作伙伴。在AIM 3中，Ikle博士将通过评估潜力来培训人类遗传学并翻译研究 GINS4在人类新生儿和2型糖尿病发病机理中的作用。 Ikle博士已有适当的事先培训 胚胎开发，遗传学和胰岛生物学，具有多个第一专作者出版物和演示文稿。 量身定制的职业发展计划是为了使Ikle博士获得新的实验技能和概念 干细胞生物学，基因编辑，转录组学和表观基因组学以及通过实践和 课程。导师Anna Gloyn博士是糖尿病遗传学，功能基因组学和胰岛细胞的领先专家 生物学。联盟人Seung Kim博士（Pancreatic Islet Development）和顾问Louis Philipson博士（单基因 糖尿病），Lori Sussel博士（胰腺胚胎学）和Julie Sneddon博士（胰腺干细胞生物学）。这 斯坦福大学的环境，包括NIH支持斯坦福糖尿病研究中心（主任：Seung博士 Kim）和孕产妇健康研究所，是协作和 创新研究。充满活力的硅谷的中心有世界一流的核心设施。总之， 预计强烈的心理，环境和培训计划将为Ikle博士做好准备以启动她 糖尿病遗传学的独立职业。拟议的研究承诺将提供机械洞察力 胰岛的胚胎开发，有可能提供机会以改善 精密医学和用于人β细胞开发的体外干细胞方案。