Endoplasmic Reticulum Stress and Diabetes

描述（由申请人提供）：内质网（ER）是一个细胞室，负责多种重要的细胞功能，包括用于分泌的新合成蛋白质的生物合成和折叠，如胰岛素。多种病理生理因素干扰内质网功能，引起内质网稳态失调，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。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，以及用于移植的分离供体细胞的死亡。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。我们这个项目的具体目标如下。目的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存活中的作用。目标3。研究TXNIP调控的促凋亡通路在¿细胞中的作用。

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.