Circadian Control of Pancreatic Beta-cell Maturation

胰腺β细胞成熟的昼夜节律控制

基本信息

批准号：
10887881
负责人：
Juan R Alvarez
金额：
$ 7.56万
依托单位：
UNIVERSITY OF PENNSYLVANIA
依托单位国家：
美国
项目类别：
财政年份：
2021
资助国家：
美国
起止时间：
2021-07-22 至 2024-10-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10887881
关键词：
Address Animals Behavior Therapy Beta Cell Binding Biochemical Biological Biological Assay Birth Cell Maturation Cell Separation Cell physiology Cells Chromatin Chronic Circadian Dysregulation Circadian Rhythms Clinical Research Complement Coupled Defect Development Diabetes Mellitus Diabetic mouse Enhancers Ensure Environment Exocytosis Family suidae Fasting Fostering Gene Expression Genes Genetic Genetic Transcription Genetic study Genomics Glucose Goals Human In Vitro Insulin Link Maintenance Measures Mediator Mentors Metabolic Methods Molecular Morphologic artifacts Mus Mutant Strains Mice Neonatal Non-Insulin-Dependent Diabetes Mellitus Periodicity Phenotype Physiological Physiology Population Process Proteins Proteome Regulation Reporter Research Research Personnel Risk Rodent Role Series Sleep Specific qualifier value Specificity Stimulus Structure Structure of beta Cell of islet Testing Therapeutic Training Training Activity Transcription Coactivator Weaning candidate identification career development circadian circadian biology circadian pacemaker diabetes mellitus genetics diabetic patient epidemiology study epigenome experience experimental study feeding fetal glucose tolerance in utero innovation insight insulin dependent diabetes mellitus onset insulin secretion insulin sensitivity islet mRNA Expression new therapeutic target novel strategies pharmacologic postnatal prevent programs promoter recruit research and development response shift work single cell technology skills stem cells therapy development transcription factor transcriptome transplantation therapy type I and type II diabetes

项目摘要

PROJECT SUMMARY/ABSTRACT Following developmental specification, pancreatic beta cells adapt to changes in the postnatal environment through functional maturation. They gain glucose-responsive insulin secretion, and gradually refine it by increasing the glucose threshold for secretion and expanding secretory capacity. While factors promoting beta cell maturation have been described, the underlying molecular mechanisms and their physiological triggers remain unclear. New insights into how beta cells acquire their mature phenotype are needed to develop efforts to curb loss of this phenotype during the onset of type 1 and type 2 diabetes, and to generate functionally mature beta cells from stem cells that can be used as transplantation therapy. The transcription factor Dec1 is a modulator of the circadian clock mechanism that is specifically activated during postnatal beta cell maturation. Dec1 binds promoter/enhancers of genes encoding key mediators of mature glucose sensing and insulin secretion, and loss of Dec1 in beta cells renders mice diabetic due to physiologically immature islets. Dr. Alvarez proposes to investigate the molecular basis for these phenotypes, by 1) examining the impact of Dec1 loss on the epigenome, transcriptome, and proteome of single pancreatic beta cells, and 2) determining the functional partners and molecular mechanisms by which Dec1 modulates beta cell maturity. These innovative experiments complement Dr. Alvarez' prior skills while conferring new training in circadian live-animal studies and single-cell technologies. A world-class team of mentors and collaborators with leading experience in these methods and in beta cell, diabetes, and circadian physiology ensures exceptional guidance. In addition, a series of formal, structured didactic and experiential training activities aimed at fostering Dr. Alvarez' development as an independent investigator are proposed. In all, the proposed research and career development activities will be critical to Dr. Alvarez developing a new independent research program focused on linking circadian biology to beta cell physiology. Results from this research program will be important to identify and exploit therapeutic opportunities to manage, prevent, or even restore the loss of mature beta cell function in diabetic patients.

项目概要/摘要遵循发育规范，胰腺β细胞适应出生后环境的变化通过功能成熟。他们获得葡萄糖反应性胰岛素分泌，并通过以下方式逐渐完善它：提高分泌的葡萄糖阈值并扩大分泌能力。虽然促进贝塔的因素已经描述了细胞成熟、潜在的分子机制及其生理触发因素仍不清楚。需要对β细胞如何获得成熟表型的新见解来开展工作在 1 型和 2 型糖尿病发作期间抑制这种表型的丧失，并在功能上产生来自干细胞的成熟β细胞，可用作移植疗法。转录因子 Dec1 是生物钟机制的调节剂，被特异性激活出生后 β 细胞成熟期间。 Dec1 结合编码关键介质的基因的启动子/增强子成熟的葡萄糖感应和胰岛素分泌以及β细胞中Dec1的缺失导致小鼠患糖尿病生理上未成熟的胰岛。阿尔瓦雷斯博士建议研究这些表型的分子基础， 1) 检查 Dec1 缺失对单个胰腺表观基因组、转录组和蛋白质组的影响 β 细胞，2) 确定 Dec1 调节的功能伙伴和分子机制 β细胞成熟度。这些创新实验补充了阿尔瓦雷斯博士先前的技能，同时提供了新的昼夜节律培训活体动物研究和单细胞技术。世界一流的导师和合作者团队在这些方法以及 β 细胞、糖尿病和昼夜生理学方面的经验确保了卓越的指导。此外，一系列正式的、结构化的教学和体验培训活动旨在建议促进阿尔瓦雷斯博士作为独立研究者的发展。总而言之，拟议的研究和职业发展活动对于阿尔瓦雷斯博士开发新的独立研究项目专注于将昼夜节律生物学与β细胞生理学联系起来。结果由此研究计划对于识别和利用治疗机会来管理、预防甚至恢复糖尿病患者成熟β细胞功能的丧失。