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 糖尿病是死亡率的主要原因和全球疾病的糖尿病，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））的鉴定。 NDM一直在了解胰腺β细胞的发展和功能 但是 口服药物不是咖喱，也不会消除每日糖尿病管理的需求。 对所有形式的糖尿病的诊断和有针对性的治疗都需要的迫切需要，包括 细胞替代策略，以改善生命的美食并减少次要并发症。 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。 和人类遗传学，体外干细胞的分化，转录组学和表观基因组学检查的作用 胰腺开发中的Gins4。 体内和体外Islett生物学，干细胞分化和AIM 1。 Jennifer Ikle，将在体外干细胞模型，基因编辑技术中与导师Anna Gloyn博士一起培训 在AIM 2中进行内分泌细胞的转录组分析。 和表观基因组学通过直接查看蛋白质和DNA相互作用wetweens4及其结合 伙伴在AIM 3中，Ikle博士将通过评估人类遗传学和翻译研究 GINS4在人类新生儿和2型糖尿病发病机理中的作用。 胚胎发展，遗传学和胰岛生物学，具有多个第一专作者出版物和存在。 职业发展计划的量身定制为启用博士。 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 课程工作。 生物学。 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） 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 综述 预计强大的指导，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。 胰岛的胚胎开发，有能力为既改进的机会提供机会 精密医学和用于人β细胞开发的体外干细胞方案。