Endoplasmic reticulum stress and diabetes

描述(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)应激导致糖尿病患者的β细胞死亡。内质网应激是由客户蛋白负荷对内质网的需求和内质网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)是一种中和内质网应激的适应性反应。内质网相关蛋白降解(ERAD)是UPR的一个组成部分，与内质网应激细胞的存活有关。 肌醇需要1(IRE1)是UPR的中枢调节因子。我们的数据表明，IRE1不仅在胰岛素的生物合成中具有重要的功能，而且大量的客户蛋白胰岛素导致β细胞中高基线水平的内质网应激。这意味着，只有内质网压力的轻微增加才可能导致β细胞死亡。Wolfram综合征(WFS)就是这样一个例子。WFS是一种罕见的青少年糖尿病，其发病机制被归因于WFS1基因的突变。这些突变大多发生在第8外显子，该外显子编码蛋白质的跨膜和C末端管腔结构域。我们假设WFS1的突变导致内质网中蛋白质的错误折叠，导致内质网应激增加，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IRE1信号在β细胞中的功能。在目标3中，我们将研究内质网应激介导的β细胞死亡的分子机制。建议的研究将阐明内质网应激与糖尿病的关系。了解这种关系将使我们更接近我们的最终目标，即开发阻止内质网应激介导的β细胞死亡的药物。

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.