ATF6 and the Beta Cell

ATF6 和 Beta 细胞

• 批准号: 10046903
• 负责人: Laura C Alonso
• 金额: $ 31.44万
• 依托单位: WEILL MEDICAL COLL OF CORNELL UNIV
• 依托单位国家: 美国
• 财政年份: 2017
• 资助国家: 美国
• 起止时间: 2017-08-01 至 2022-07-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10046903
• 关键词: ATF6 gene; Address; Adenoviruses; Attention; Autoimmunity; Back; Beta Cell; Bioinformatics; Biology; Cell Count; Cell Death; Cell Differentiation process; Cell Proliferation; Cell Survival; Cell physiology; Cells; Cellular Stress; Data; Diabetes Mellitus; Disease; Failure; Feasibility Studies; Functional disorder; Genetic Transcription; Glucose; Goals; Growth Factor; Hand; Health; Human; Hyperglycemia; Indiana; Insulin; Insulin Resistance; Knowledge; Lead; Length; Link; LoxP-flanked allele; Maintenance; Malignant neoplasm of liver; Mediating; Methods; Modeling; Mus; Natural regeneration; Non-Insulin-Dependent Diabetes Mellitus; Nuclear; Overnutrition; Pathogenesis; Pathway interactions; Peptides; Physiological; Physiological Adaptation; Plasmids; Play; Production; Proliferating; Proteins; Regulation; Research; Risk; Rodent; Role; Signal Pathway; Signal Transduction; Specificity; Stimulus; Structure of beta Cell of islet; Tissues; Translations; Work; blood glucose regulation; carcinogenicity; deep sequencing; diabetes risk; diabetogenic; endoplasmic reticulum stress; experience; experimental study; functional improvement; functional restoration; human tissue; improved; in vivo; islet; novel; novel therapeutic intervention; overexpression; pancreatic islet function; response; small hairpin RNA; small molecule inhibitor; stress tolerance; tool; transcription factor

ABSTRACT Diabetes mellitus results when pancreatic beta cells fail to produce enough insulin to maintain glucose homeostasis, either due to beta cell destruction (T1D) or insulin resistance (T2D). Beta cell failure can result from loss of beta cell number, reduced insulin secretory function, or both. Two important goals in diabetes research are to understand the causes of islet failure and to find therapies that restore functional beta cells. To date, my group has focused on identifying ways to increase beta cell mass by inducing proliferation of endogenous beta cells. We recently made the surprising, but in retrospect logical, observation that engaging mild ER stress stimulates beta cell proliferation (Sharma et al, JCI 2015). This concept suggests a beta-cell-autonomous explanation for compensatory beta cell proliferation in response to increased insulin demand. We have traced the proliferative signal to Atf6, which is one of three canonical UPR signaling pathways. Stepping back, Atf6 is a transcription factor which may play an important role in pancreatic islet function but whose biology is, to date, relatively unexplored in this tissue. Loss of Atf6 has been linked to human diabetes risk, and experiments in mice suggest that beta cell Atf6 activity protects against diabetogenic insults. Current understanding of Atf6 biology suggests several possible mechanisms by which Atf6 may be beneficial for beta cell health, including not only proliferation but also insulin production and secretion, maintenance of beta cell differentiation status, and promoting beta cell survival. Experiments in this project will explore Atf6 roles in healthy beta cell adaptation to insulin demand, assessing both proliferation and function. We will define mechanisms downstream of Atf6, using both candidate and unbiased approaches to identify Atf6 transcription targets in mouse and human islets. Finally, we will determine how Atf6 loss undermines beta cell capacity to stand up to diabetogenic stimuli. To accomplish these studies we have assembled a strong team of beta cell ER stress experts (Peter Arvan, Raghu Mirmira, Fumi Urano) and an Atf6 expert (Luke Wiseman). With technical support from the UMass MMPC (Jason Kim), the Indiana Diabetes Research Center (Raghu Mirmira), and the UMass Deep Sequencing and Bioinformatics cores (Maria Zapp, Alper Kucukural, Nick Merowsky) we have all the tools in hand to move this important work forward.

摘要 当胰腺β细胞不能产生足够的胰岛素来维持胰岛素分泌时， 葡萄糖稳态，由于β细胞破坏（T1D）或胰岛素抵抗（T2D）。β细胞 衰竭可由β细胞数量的丧失、胰岛素分泌功能的降低或两者引起。两 糖尿病研究的重要目标是了解胰岛功能衰竭的原因， 恢复功能性β细胞的疗法。到目前为止，我的团队一直专注于确定 通过诱导内源性β细胞增殖增加β细胞质量。我们最近做了 令人惊讶的，但回顾起来合乎逻辑的，观察到参与轻度ER应激刺激β细胞 增殖（Sharma等，JCI 2015）。这个概念提出了一个β细胞自主的解释， 这是由于胰岛素需求增加而引起的代偿性β细胞增殖。我们追踪了 Atf6是三种典型的UPR信号通路之一。后退一步， Atf6是一种转录因子，可能在胰岛功能中起重要作用，但其 迄今为止，生物学在该组织中相对未被探索。Atf6的缺失与人类 糖尿病风险，小鼠实验表明，β细胞Atf6活性可以防止糖尿病风险。 致糖尿病的侮辱目前对Atf6生物学的理解提出了几种可能的机制 Atf6可能对β细胞健康有益，不仅包括增殖，还包括胰岛素 生产和分泌，维持β细胞分化状态，促进β细胞 生存该项目的实验将探索Atf6在健康β细胞适应胰岛素中的作用 需求，评估扩散和功能。我们将定义Atf6下游的机制， 使用候选和无偏的方法来鉴定小鼠中的Atf6转录靶标， 人类的小岛最后，我们将确定Atf6的缺失如何破坏β细胞的抵抗能力。 致糖尿病的刺激为了完成这些研究，我们组建了一个强大的β细胞ER团队， 压力专家（Peter Arvan，Raghu Mirmira，Fumi Urano）和Atf6专家（Luke Wiseman）。与 来自麻省大学MMPC（Jason Kim）、印第安纳州糖尿病研究中心的技术支持 （Raghu Mirmira）和马萨诸塞大学深度测序和生物信息学核心（Maria Zapp，Alper Kucukural，Nick Merowsky）我们拥有所有的工具来推动这项重要的工作。