ATF6 and the Beta Cell

摘要 当胰岛β细胞不能产生足够的胰岛素来维持时，就会发生糖尿病 葡萄糖稳态，由β细胞破坏(T1D)或胰岛素抵抗(T2D)引起。β细胞 失败的原因可能是β细胞数量减少，胰岛素分泌功能降低，或者两者兼而有之。二 糖尿病研究的重要目标是了解胰岛衰竭的原因并找到 恢复功能贝塔细胞的疗法。到目前为止，我的团队一直专注于确定 通过诱导内源性β细胞增殖来增加β细胞质量。我们最近制作了 令人惊讶，但回想起来合乎逻辑的是，观察到参与轻微的内质网应激刺激β细胞 扩散(Sharma等人，JCI，2015年)。这一概念提出了一种β细胞自主的解释 胰岛素需求增加时的代偿性β细胞增殖。我们已经追踪到了 增殖信号转导ATF6，这是三个典型的UPR信号通路之一。退后一步， ATF6是一种转录因子，可能在胰岛功能中发挥重要作用，但其 到目前为止，生物学在这一组织中的研究相对较少。ATF6基因的缺失与人类 糖尿病风险，在小鼠身上的实验表明，β细胞ATF6活性可以预防 导致糖尿病的侮辱。目前对ATF6生物学的理解提出了几种可能的机制 通过ATF6可能有益于β细胞的健康，不仅包括增殖，还包括胰岛素 产生和分泌，维持β细胞分化状态，促进β细胞 生死存亡。该项目的实验将探索ATF6在健康的β细胞对胰岛素适应中的作用。 需求，评估扩散和功能。我们将定义Atf6下游的机制， 用候选和无偏倚方法识别小鼠和小鼠的ATF6转录靶点 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 糖尿病引起的刺激。为了完成这些研究，我们组建了一支强大的β细胞内质网团队 压力专家(彼得·阿尔万、拉古·米尔米拉、富米·乌拉诺)和ATF6专家(卢克·怀斯曼)。使用 印第安纳州糖尿病研究中心MMPC(Jason Kim)的技术支持 和UMASS深度测序和生物信息学核心(Maria Zapp，Alper 库库拉尔，尼克·默洛夫斯基)我们手中有所有的工具来推动这项重要的工作。

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.