Endoplasmic reticulum stress and diabetes

描述（由申请人提供）：β细胞死亡是糖尿病的重要致病因素。我们的数据表明，内质网（ER）应激有助于糖尿病患者的β细胞死亡。ER应激是由客户蛋白负载对ER的需求与ER满足该需求的能力之间的不平衡引起的。“未折叠蛋白反应”（UPR）是一种抵消ER应激的适应性反应。ER相关蛋白降解（ERAD）是UPR的一个组成部分，有助于ER应激细胞的存活。 肌醇需求1（IRE 1）是UPR的核心调节因子。我们的数据表明，IRE 1不仅在胰岛素生物合成中具有重要功能，而且客户蛋白胰岛素的高负荷导致β细胞中高基线水平的ER应激。这意味着只有轻微的额外增加ER应激可能导致β细胞死亡。这就是Wolfram综合征（WFS）。WFS是一种罕见的青少年糖尿病，其发病机制归因于WFS 1基因突变。这些突变中的大多数发生在外显子8，其编码蛋白质的跨膜和C-末端管腔结构域。我们假设WFS 1突变导致ER中蛋白质的错误折叠，导致ER应激增加，从而导致β细胞死亡。 在目标1中，我们将研究ERAD在WFS中β细胞死亡中的作用。在目标2中，我们将确定IRE 1信号传导在β细胞中的功能。在目标3中，我们将研究ER应激介导的β细胞死亡的分子机制。这些研究将有助于阐明内质网应激与糖尿病的关系。理解这种关系将使我们更接近开发阻断ER应激介导的β细胞死亡的药物的最终目标。

DESCRIPTION (provided by applicant): Beta-cell death is an important pathogenic element in diabetes. Our data demonstrate that endoplasmic reticulum (ER) stress contributes to beta-cell death in patients with diabetes. ER stress is caused by imbalance between the demand placed on the ER by the load of client proteins and the ability of the ER to meet that demand. The "unfolded protein response" (UPR) is an adaptive response that counteracts ER stress. ER-associated protein degradation (ERAD), a component of the UPR, contributes to the survival of ER-stressed cells. Inositol Requiring 1 (IRE1) is a central regulator of the UPR. Our data show not only that IRE1 has an important function in insulin biosynthesis, but that a heavy load of client protein, insulin, causes a high baseline level of ER stress in beta-cells. This means that only a slight additional increase in ER stress is likely to lead to beta-cell death. Such an example is Wolfram syndrome (WFS). The pathogenesis of WFS, a rare form of juvenile diabetes, has been attributed to mutations in the WFS1 gene. Most of those mutations occur in exon 8, which encodes the protein's transmembrane and C-terminal luminal domains. We hypothesize that mutations in WFS1 lead to misfolding of protein in the ER, cause an increase in ER stress, and consequently lead to beta-cell death. In Aim 1, we will examine the roles of ERAD in beta-cell death in WFS. In Aim 2, we will determine the function of IRE1 signaling in beta-cells. In Aim 3, we will study the molecular mechanisms of ER stress-mediated beta-cell death. The proposed studies will elucidate the relationship between ER stress and diabetes. Understanding this relationship will move us closer to our ultimate goal of developing drugs that block ER stress-mediated beta-cell death.