Mechanism of PANDER Induced Apoptosis

胰腺衍生因子（PANDER）是最近鉴定的胰腺特异性的235个氨基酸的蛋白质， 分泌信号肽PANDER信息主要表达在胰岛中， 胰腺，小肠和前列腺中的程度较小。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。额外 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 β、肿瘤坏死因子-a和干扰素-y可以促进 通过凋亡和坏死的细胞死亡。然而，启动p-细胞死亡的确切机制， 自身免疫性糖尿病尚未确定，PANDER可能参与其中。另外由于 到最近发现的PANDER，其功能仍然未知。提出的假设背后的假设 研究表明，胰岛内细胞因子诱导的PANDER上调下调了胰岛内的PANDER表达。 p21的抗凋亡蛋白，并一致地增加caspase-3的表达， 诱导胰岛细胞凋亡，影响I型糖尿病的发病机制。两个主要目标是。 (1)确定细胞因子调节PANDER诱导胰岛细胞凋亡的机制;（2）确定PANDER在胰岛细胞凋亡中的作用 PANDER在I型糖尿病发病机制中的作用，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：表征PANDER表达下调对细胞因子诱导的细胞凋亡的影响。 胰岛细胞凋亡 目的3：阐明PANDER诱导的细胞凋亡信号通路，重点是作用 候选基因和PANDER受体。 目的4：评估过表达在小鼠模型中诱导肿瘤细胞凋亡的作用。 糖尿病表型 相关性-糖尿病目前是一个严重且迅速增长的医疗保健问题，影响约 在美国有1800万人。1型糖尿病是一种常见的糖尿病。 产生胰岛素的胰岛细胞。胰岛细胞破坏的确切机制尚不清楚， 确定了一种新的胰岛产生的分子PANDER在这一破坏性过程中的作用。

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-1p, tumor necrosis factor-a, and interferon-y can promote cell death via apoptosis and necrosis. However, the precise mechanisms initiating p-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. Thetwomajor 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.