Mechanism of PANDER Induced Apoptosis

描述（由申请人提供）： 胰腺衍生因子（PANDER）是最近发现的一种胰腺特异性蛋白质，由235个氨基酸组成，具有分泌信号肽。PANDER信息主要在胰腺的胰岛中表达，在小肠和前列腺中表达较少。基于保守的细胞因子二级结构，PANDER被鉴定并预测为一种新的胰腺特异性细胞因子。另外的研究显示外源性添加和腺病毒递送的细胞内PANDER能够诱导原代胰岛和各种胰岛细胞系的凋亡。与PANDER对胰岛的生物学效应相似，各种炎症细胞因子如白细胞介素-1（、肿瘤坏死因子-（和干扰素-（可通过凋亡和坏死促进细胞死亡。然而，引发自身免疫性糖尿病β-细胞死亡的确切机制尚未确定，PANDER可能参与其中。此外，由于最近发现的PANDER的功能仍然是未知的。提出的研究背后的假设是，细胞因子诱导的胰岛内PANDER上调下调p21的抗凋亡蛋白，并一致地增加caspase-3的表达，随后诱导胰岛细胞凋亡，并影响I型糖尿病的发病机制。两大目标是：（1）确定细胞因子调节PANDER诱导胰岛细胞凋亡的机制;和（2）确定PANDER在I型糖尿病发病机制中的作用，具有四个具体目标： 目的1：确定细胞因子是否上调小鼠胰岛中内源性和分泌的PANDER。 目的2：研究PANDER基因表达下调对细胞因子诱导的胰岛细胞凋亡的影响。 目的3：通过对候选基因和PANDER受体的研究，阐明PANDER诱导细胞凋亡的信号通路。 目的4：评价过表达在小鼠模型中诱导糖尿病表型的作用。 糖尿病目前是一个严重且快速增长的医疗保健问题，影响着美国约1800万人。1型糖尿病是一种常见的糖尿病，它的发病机制是胰岛素分泌紊乱。胰岛细胞破坏的确切机制尚不清楚，我们的资助确定了一种称为PANDER的新型胰岛产生分子在这一破坏性过程中的作用。

DESCRIPTION (provided by applicant): Pancreatic Derived Factor (PANDER) is a recently identified pancreas-specific 235 amino acid protein with a secretion signal peptide. PANDER message is dominantly expressed in the islets of Langerhans of the pancreas, and to a lesser extent in the small intestine and prostate. Based on conserved cytokine secondary structures, PANDER was identified and predicted to be a novel, pancreas-specific cytokine. Additional studies revealed exogenously added and adenoviral delivered intracellular PANDER is capable of inducing apoptosis of primary islets and various islet cell lines. Similar to PANDER'S biological effects on islets, various inflammatory cytokines such as interleukin-1(, tumor necrosis factor-(, and interferon-( can promote cell death via apoptosis and necrosis. However, the precise mechanisms initiating (-cell death in autoimmune diabetes have yet to be determined and PANDER may be potentially involved. In addition, due to the recent discovery of PANDER the function is still unknown. The hypothesis behind the proposed research is that the cytokine induced upregulation of PANDER within islets downregulates the antiapoptotic protein of p21 and concordantly increases caspase-3 expression which subsequently induces islet cell apoptosis and impacts the pathogenesis of type I diabetes. The two major goals are: (1) identify the mechanism of cytokine regulated PANDER induced islet apoptosis; and (2) determine the role of PANDER in the pathogenesis of type I diabetes, with four specific aims: Aim 1: Determine if cytokines upregulate endogenous and secreted PANDER in murine islets. Aim 2: Characterize the effects of downregulation of PANDER expression on cytokine induced islet apoptosis. Aim 3: Elucidate the PANDER induced apoptotic signaling pathways by focusing on the roles of candidate genes and the PANDER receptor. Aim 4: Evaluate the role of overexpression in a mouse model with regard to induction of a diabetic phenotype. Relevance- Diabetes is currently a serious and rapidly growing healthcare problem impacting approximately 18 million people in the United States. A type of diabetes known as type 1 diabetes results in the destruction of insulin-producing islet cells. The exact mechanism of islet-cell destruction is unknown and our grant identifies the role of a novel islet-produced molecule known as PANDER in this destructive process.