Endoplasmic Reticulum Stress and Diabetes

描述（由申请人提供）：内质网（ER）是负责多种重要细胞功能的细胞区室，包括用于分泌的新合成蛋白质（如胰岛素）的生物合成和折叠。多种病理和生理因素干扰ER功能，导致ER稳态失调，导致ER应激。细胞通过激活ER应激信号通路来应对ER应激，也称为未折叠蛋白反应（UPR）。这种激活导致ER稳态的恢复并保护细胞免受ER应激。越来越多的证据表明，ER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，以及用于移植的分离供体细胞的死亡。 我们的目标是了解ER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。目标1.研究Wolfram综合征中UPR的失调。目标2.以确定AATF在人和小鼠原代胰岛体内存活中的作用。目标3。探讨TXNIP在细胞凋亡中的作用。 公共卫生相关性：糖尿病是一组由胰岛素绝对缺乏（1型糖尿病）或相对缺乏（2型糖尿病）引起的高血糖症定义的疾病。胰岛素是胰腺细胞分泌的一种激素，具有降低血糖的功能。越来越多的证据表明，由内质网（ER）中未折叠和错误折叠蛋白质的积累引起的细胞应激（称为ER应激）与1型和2型糖尿病以及Wolfram综合征（糖尿病的遗传形式）进展期间的细胞功能障碍和死亡直接相关。为了抵消ER应激，细胞激活称为未折叠蛋白反应（UPR）的细胞信号传导途径。根据压力条件的性质，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清楚，但涉及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，我们研究了这种普遍定期审议在生与死之间的平衡行为及其机制。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亡原因之一，2007年影响2360万人，总经济成本为1740亿美元。我们已经确定了普遍定期审议的重要生存和死亡内容。研究这些分子在内质网应激和细胞中的调节和功能可能揭示慢性内质网应激如何诱导细胞死亡的新信息，以及糖尿病预防或治疗的新靶点。

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.