Mechanism of PANDER Induced Apoptosis

PANDER诱导细胞凋亡的机制

• 批准号: 7209796
• 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
• 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
• 来源: https://reporter.nih.gov/project-details/7209796
• 关键词: Amino Acids; Apoptosis; Apoptotic; Autoimmune Diabetes; Biological; CDKN1A gene; Candidate Disease Gene; Cell Death; Cell Line; Cells; Cyclin A; Diabetes Mellitus; Dose; Down-Regulation; Enzymes; Genes; Genetic; Goals; Grant; Healthcare; Inflammatory; Insulin; Insulin-Dependent Diabetes Mellitus; Interferons; Interleukin-1; Islet Cell; Islets of Langerhans; Link; Molecular Profiling; Mus; Necrosis; Numbers; Pancreas; Pathogenesis; Pathway Analysis; Peptide Signal Sequences; Personal Satisfaction; Phenotype; Process; Prostate; Protein Overexpression; Proteins; Repression; Research; Role; Signal Pathway; Small Intestines; Structure; Time; Treatment Factor; Tumor Necrosis Factor-alpha; Tumor Necrosis Factors; United States; Up-Regulation; apoptosis inducing factor; base; caspase-3; cell type; cytokine; diabetic; human TNF protein; improved; insulinoma; islet; mouse model; novel; oncoprotein p21; receptor

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.

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 信息主要在胰腺的朗格汉斯岛中表达，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型的胰腺特异性细胞因子。其他研究表明，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 对胰岛的生物效应类似，各种炎症细胞因子，如白介素-1(、肿瘤坏死因子-(和干扰素-()，可以通过凋亡和坏死促进细胞死亡。然而，自身免疫性糖尿病中启动(-细胞死亡)的精确机制尚未确定，并且 PANDER 可能参与其中，此外，由于最近发现 PANDER，其功能仍然未知，拟议研究背后的假设是细胞因子诱导上调。胰岛内的 PANDER 下调 p21 的抗凋亡蛋白，并相应增加 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。两个主要目标是：（1）确定细胞因子调节的 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，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胰岛细胞凋亡的影响。 目标 3：通过关注候选基因和 PANDER 受体的作用，阐明 PANDER 诱导的细胞凋亡信号通路。 目标 4：评估小鼠模型中过度表达对于诱导糖尿病表型的作用。 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，影响着美国约 1800 万人。一种称为 1 型糖尿病的糖尿病会导致产生胰岛素的胰岛细胞遭到破坏。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名为 PANDER 的新型胰岛产生分子在这一破坏过程中的作用。