Mechanism of PANDER Induced Apoptosis

PANDER诱导细胞凋亡的机制

基本信息

批准号：
7781296
负责人：
BRANT Roger BURKHARDT
金额：
$ 13.39万
依托单位：
CHILDREN'S HOSP OF PHILADELPHIA
依托单位国家：
美国
项目类别：
财政年份：
2006
资助国家：
美国
起止时间：
2006-04-01 至 2011-03-31
项目状态：
已结题

项目摘要

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.

胰腺衍生因子（Pander）是最近确定的胰腺特异性235氨基酸蛋白分泌信号肽。 pander信息主要在兰格汉的胰岛中表达胰腺，在小肠和前列腺中的程度较小。基于配置的细胞因子次要结构，pander被鉴定出来并被预测为一种新型的胰腺特异性细胞因子。额外的研究表明，外源添加，腺病毒递送的细胞内pander能够诱导原代小岛和各种胰岛细胞系的凋亡。类似于Pander对小岛的生物学影响，各种炎症细胞因子，例如白介素1P，肿瘤坏死因子-A和干扰素-Y可以促进细胞死亡通过细胞凋亡和坏死。但是，确切的机制在自身免疫性糖尿病尚未确定，并且可能涉及pander。另外，应有的对于最近发现的pander，该功能仍然未知。提议背后的假设研究是，细胞因子在胰岛内诱导的pand诱导的上调下调了 p21的抗凋亡蛋白和一致增加的caspase-3表达，随后诱导胰岛细胞凋亡并影响I型糖尿病的发病机理。 Thetwomajor目标是。（1）确定细胞因子调节的胰岛诱导胰岛凋亡的机制；（2）确定角色在I型糖尿病的发病机理中的Pander，具有四个特定的目的： AIM 1：确定细胞因子是否上调了鼠胰岛中的内源性和分泌的pander。 AIM 2：表征下调pander表达对细胞因子诱导的影响的影响胰岛凋亡。 „ AIM 3：通过关注角色来阐明Pander引起的凋亡信号传导途径候选基因和pander受体。 AIM 4：评估过表达在小鼠模型中的作用糖尿病表型。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，影响大约美国有1800万人。一种糖尿病称为1型糖尿病会导致破坏产生胰岛素的胰岛细胞。胰岛破坏的确切机制未知，我们的授予在这种破坏性过程中鉴定了一种新型胰岛产生的分子的作用。