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）是一种最近鉴定出的具有分泌信号肽的胰腺特异性氨基酸蛋白。 Pander信息主要在胰腺的Langerhans的胰岛中表达，并且在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，鉴定出Pander并被预测为一种新型的胰腺特异性细胞因子。进一步的研究表明，外源添加，腺病毒递送的细胞内pander能够诱导原代胰岛和各种胰岛细胞系的凋亡。与Pander对胰岛的生物学作用相似，各种炎症细胞因子，例如介育因子（肿瘤坏死因子因子）（可以通过凋亡和坏死来促进细胞死亡 - 但是，确切的机制启动的精确机制（ - 在自给自足的糖尿病中还可以确定的疾病，还可以确定疾病，并且还需要确定疾病。拟议研究的假设未知。细胞因子在胰岛内诱导的pander诱导的上调p21的抗凋亡蛋白，并一致增加caspase-3表达，随后诱导胰岛细胞凋亡，并影响I型糖尿病的病原体。凋亡；（2）确定pander在I型糖尿病的发病机理中的作用，有四个特定的目的： 目标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pander表达下调对细胞因子诱导的胰岛凋亡的影响。 AIM 3：通过关注候选基因和pander受体的作用来阐明pander诱导的凋亡信号通路。 目标4：评估过度表达在诱导糖尿病表型方面的作用。 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，影响了美国约1800万人。一种称为1型糖尿病的糖尿病会导致胰岛素产生的胰岛细胞破坏。胰岛细胞破坏的确切机制尚不清楚，我们的赠款在这种破坏性过程中确定了一种新型胰岛产生的分子的作用。