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Circadian Control of Pancreatic Beta-cell Maturation by Dec1

12 月 1 日之前胰腺 β 细胞成熟的昼夜节律控制

基本信息

批准号：
10284086
负责人：
Juan R Alvarez
金额：
$ 10.27万
依托单位：
HARVARD UNIVERSITY
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 2021-12-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10284086
关键词：
Address Animals Behavior Therapy Beta Cell Binding Biochemical Biological Biological Assay Biology Birth Cell Maturation Cell physiology Cells Chromatin Chronic 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 Lead Link Maintenance Measures Mediator of activation protein 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 Specificity Stimulus Structure Structure of beta Cell of islet Testing Therapeutic Training Training Activity Transcription Coactivator Weaning behavioral pharmacology career development circadian 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 novel strategies postnatal prevent programs promoter recruit research and development response shift work single cell technology skills stem cells therapeutic target therapy development transcription factor transcriptome transplantation therapy

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.

项目总结/文摘