Circadian Control of Pancreatic Beta-cell Maturation

项目总结/摘要 随着发育的规范，胰腺β细胞适应出生后环境的变化 通过功能成熟。他们获得葡萄糖响应性胰岛素分泌，并逐渐完善它， 增加葡萄糖分泌阈值和扩大分泌能力。虽然促进β 已经描述了细胞成熟，潜在的分子机制及其生理触发因素 仍然不清楚。需要对β细胞如何获得其成熟表型的新见解来发展努力 以抑制1型和2型糖尿病发作期间这种表型的丧失，并在功能上产生 从干细胞中提取成熟的β细胞，可用于移植治疗。 转录因子Dec 1是生物钟机制的调节剂， 在出生后的β细胞成熟期。Dec 1结合编码以下关键介质的基因的启动子/增强子： 成熟的葡萄糖感知和胰岛素分泌，以及β细胞中Dec 1的缺失使小鼠患糖尿病， 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， 通过1）检查Dec 1缺失对单个胰腺癌细胞表观基因组、转录组和蛋白质组的影响， β细胞，以及2）确定Dec 1调节的功能伴侣和分子机制 β细胞成熟 这些创新的实验补充了阿尔瓦雷斯博士先前的技能，同时赋予了昼夜节律的新训练。 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， 在这些方法和β细胞、糖尿病和昼夜生理学方面的经验确保了 指导此外，还举办了一系列正式的、有组织的教学和体验式培训活动， 促进阿尔瓦雷斯博士作为独立调查员的发展。 总之，拟议的研究和职业发展活动将是至关重要的阿尔瓦雷斯博士开发一个新的 一个独立的研究项目，专注于将昼夜节律生物学与β细胞生理学联系起来。结果从这个 研究计划将是重要的，以确定和利用治疗的机会，以管理，预防，甚至 恢复糖尿病患者成熟β细胞功能的丧失。

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.