Endoplasmic Reticulum Stress and Diabetes

描述(申请人提供)：内质网(ER)是一个细胞室，负责多种重要的细胞功能，包括新合成的蛋白质的生物合成和折叠，以供分泌，如胰岛素。多种病理生理因素干扰内质网功能，导致内质网稳态失调，导致内质网应激。细胞通过激活内质网应激信号通路来应对内质网应激，也称为未折叠蛋白反应(UPR)。这种激活导致内质网稳态的恢复，并保护细胞免受内质网应激的影响。越来越多的证据表明，内质网应激介导的细胞死亡在1型和2型糖尿病的发病机制中起作用，以及用于移植的孤立供体细胞的死亡。我们的目标是了解内质网应激在细胞死亡和糖尿病发展中的作用。我们对这个项目的具体目标如下。目的1.研究Wolfram综合征中UPR的调节失调。目的：探讨AATF在人和小鼠原代胰岛存活中的作用。目的：研究血栓素NIP(TXNIP)对细胞促凋亡途径的调节作用。 公共卫生相关性：糖尿病是一组疾病，定义为绝对缺乏胰岛素(1型糖尿病)或相对缺乏胰岛素(2型糖尿病)引起的高血糖。胰岛素是一种由胰腺细胞分泌的荷尔蒙，具有降低血糖的作用。越来越多的证据表明，由内质网(ER)中未折叠和错误折叠的蛋白质积累引起的细胞应激，称为内质网应激，与1型和2型糖尿病以及糖尿病的一种遗传形式--Wolfram综合征的进展过程中的细胞功能障碍和死亡直接相关。为了对抗内质网应激，细胞激活称为未折叠蛋白反应(UPR)的细胞信号通路。根据应激状态的性质，UPR要么保护细胞，要么促进它们的死亡。这种转换的机制还不是很清楚，但涉及到UPR调节的适应性和凋亡因子之间的平衡。在这项拨款申请中，我们研究了UPR在生死之间的平衡行为及其涉及的机制。这一领域对于理解糖尿病进展过程中细胞死亡的机制尤为重要。糖尿病是美国十大死因之一，2007年影响2360万人，总经济损失达1,740亿美元。我们已经确定了普遍定期审议的重要生存和死亡部分。在内质网应激和细胞的背景下研究这些分子的调节和功能可能会揭示关于慢性内质网应激如何诱导细胞死亡的新信息，并可能为糖尿病的预防或治疗提供新的靶点。

DESCRIPTION (provided by applicant): The endoplasmic reticulum (ER) is a cellular compartment responsible for multiple important cellular functions including the biosynthesis and folding of newly synthesized proteins destined for secretion, such as insulin. Myriad pathological and physiological factors perturb ER function and cause dysregulation of ER homeostasis, leading to ER stress. Cells cope with ER stress by activating the ER stress signaling pathways, also known as the unfolded protein response (UPR). This activation results in restoration of ER homeostasis and protects cells from ER stress. Increasing evidence indicates that ER-stress-mediated ¿-cell death has a role in the pathogenesis of type 1 and type 2 diabetes, as well as the death of isolated donor ¿ cells for transplantation. Our goal is to understand the role of ER stress in ¿ cell death and development of diabetes. Our specific aims for this project are as follows. Aim 1. to investigate misregulation of the UPR in Wolfram syndrome. Aim 2. to determine the role of AATF in the survival of human and mouse primary islets in vivo. Aim 3. to study the role of pro-apoptotic pathway regulated by TXNIP in ¿ cells. PUBLIC HEALTH RELEVANCE: Diabetes is a group of disorders defined by hyperglycemia caused by an absolute deficiency (type 1 diabetes) or a relative deficiency of insulin (type 2 diabetes). Insulin, a hormone secreted from pancreatic ¿ cells, functions in lowering blood glucose. Increasing evidence indicates that cellular stress caused by the accumulation of unfolded and misfolded proteins in the endoplasmic reticulum (ER), termed ER stress, is directly related to ¿ cell dysfunction and death during the progression of type 1 and type 2 diabetes, and Wolfram syndrome, a genetic form of diabetes. To counteract ER stress, ¿ cells activate cellular signaling pathways termed the unfolded protein response (UPR). Depending on the nature of the stress condition, the UPR either protects ¿ cells or promotes their death. The mechanisms of this switch are not well understood but involve the balance between adaptive and apoptotic factors regulated by the UPR. In this grant application, we study this UPR balancing act between life and death and the mechanisms involved. This area is especially important in understanding the mechanisms of ¿ cell death during the progression of diabetes. Diabetes is one of the top ten causes of death in the U.S. affecting 23.6 million people with a total economic cost of $174 billion in 2007. We have identified important survival and death components of the UPR. To study the regulation and function of these molecules in the context of ER stress and ¿ cells may reveal new information on how chronic ER stress induces ¿ cell death and perhaps novel targets for diabetes prevention or treatment.