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) 是最近发现的一种胰腺特异性蛋白质，由 235 个氨基酸组成， PANDER 信号主要在胰岛中表达。胰腺，以及较小程度的小肠和前列腺基于保守的细胞因子次级。结构，PANDER 被鉴定并预测为一种新型的胰腺特异性细胞因子。研究表明，外源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 对胰岛的生物学作用类似，多种炎性细胞因子如白细胞介素-1p、肿瘤坏死因子-a、干扰素-y等可促进细胞通过凋亡和坏死而死亡然而，引发p细胞死亡的精确机制。自身免疫性糖尿病尚未确定，此外，PANDER 可能也参与其中。就最近发现的 PANDER 功能而言，其背后的假设仍然未知。研究表明，细胞因子诱导胰岛内 PANDER 上调，从而下调 p21 的抗凋亡蛋白并一致增加 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。 (1) 确定细胞因子调节 PANDER 诱导胰岛细胞凋亡的机制；以及 (2) 确定其作用； PANDER 在 I 型糖尿病发病机制中的研究，有四个具体目标： ¿目标 1：确定细胞因子是否上调小鼠胰岛中的内源性和分泌性 PANDER。 ¿目标 2：表征 PANDER 表达下调对细胞因子诱导的影响胰岛细胞凋亡。 ¿目标 3：通过关注作用来阐明 PANDER 诱导的细胞凋亡信号通路候选基因和 PANDER 受体。 ¿目标 4：评估小鼠模型中过度表达对于诱导糖尿病表型。相关性 - 糖尿病目前是一个严重且快速增长的医疗保健问题，影响约美国有 1800 万人患有 1 型糖尿病。胰岛细胞破坏的确切机制尚不清楚，我们的资助也不清楚。确定了一种由胰岛产生的新型分子 PANDER 在这一破坏过程中的作用。