Role of Annexin II in Peripheral Vas

膜联蛋白 II 在外周血管中的作用

• 批准号: 6901465
• 负责人: RICHARD R VAILLANCOURT
• 金额: $ 16.25万
• 依托单位: UNIVERSITY OF ARIZONA
• 依托单位国家: 美国
• 财政年份: 2005
• 资助国家: 美国
• 起止时间: 2005-04-01 至 2010-03-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6901465
• 关键词: annexins; arsenic; biological signal transduction; biomarker; environmental exposure; environmental toxicology; enzyme activity; genetically modified animals; homocysteine; laboratory mouse; methylation; peripheral blood vessel disorder; plasmin; plasminogen activator inhibitors; posttranslational modifications; serine threonine protein kinase

Arsenic (As) is an inorganic environmental contaminant of major concern due to its ubiquitous presence. Chronic exposure to arsenic frequently results in peripheral vascular disease, as well as skin, lung, bladder, and kidney cancer. Recent evidence demonstrates that arsenite inhibits the production of plasmin which is necessary to dissolve blood clots in the vasculature. Our published studies with arsenic have demonstrated that the serine/threonine kinase, MEKK4, is involved in arsenic signal transduction, along with the calcium binding protein, annexin II. To understand the molecular mechanism by which arsenic causes its deleterious effects on the vascular system and how the activity of annexin II contributes to arsenic toxicity, our efforts have focused on characterizing the proteins that interact with and are regulated by annexin II. The hypothesis of this proposal is that annexin II plays a role in promoting arsenic-dependent peripheral vascular disease by modulating the formation of plasmin. To test this hypothesis, we propose the following specific aims: 1. To characterize arsenic-dependent post-translational modifications of annexin II. We propose that arsenic methylation produces homocysteine, which chemically modifies annexin II, thus inhibiting the production of plasmin and promoting clotting of the microvasculature. We propose that homocysteine-annexin II may be an indicator of arsenic exposure and we will explore the possibility of using homocysteine-annexin II as a biomarker. 2. To characterize the interaction between annexin II and MEKK4. Our data indicate interaction between annexin II and MEKK4, resulting in MEKK4 activity. Since MEKK4 appears to function downstream of annexin II, the biochemical association between these proteins will be mapped to specific domains. 3. To characterize arsenic-dependent regulation of PAI-1 and PAI-2. We propose that the ERK MAP kinase signaling pathway, regulated by annexin II and MEKK4, may be a mechanism for arsenic-dependent regulation of PAI expression. 4. To assess specific functions of annexin II. We will create a tissue-specific knockout mouse, selectively disrupting annexin II expression in smooth muscle cells, to evaluate arsenic toxicity in a whole animal. The proposed research will provide a further understanding of the importance of the arsenic-induced signaling processes and how it adversely affects the peripheral vascular system and promotes tissue injury.

砷（AS）由于其无处不在，是主要关注的无机环境污染物。长期暴露于砷经常会导致外周血管疾病以及皮肤，肺，膀胱和肾癌。最近的证据表明，砷矿会抑制纤溶酶的产生，这是溶解脉管系统中血凝块的必要条件。我们对砷的发表研究表明，丝氨酸/苏氨酸激酶Mekk4是 参与砷信号转导，以及钙结合蛋白Annexin II。为了了解砷对血管系统产生有害作用的分子机制，以及膜联蛋白II的活性如何促进砷毒性，我们的努力集中在表征与附属蛋白II相互作用和调节的蛋白质。该提议的假设是，膜联蛋白II在促进砷依赖性方面起作用 通过调节纤溶酶的形成，外周血管疾病。为了检验这一假设，我们提出了以下特定目的：1。表征依赖砷的交流后修饰。我们建议砷甲基化产生同型半胱氨酸，从而化学修饰膜联蛋白II，从而抑制纤溶酶的产生并促进微脉管系统的凝结。我们建议同型半胱氨酸 - 阿内克斯蛋白II可能是砷暴露的指标，我们将探索使用同型半胱氨酸 - 纳米蛋白II作为生物标志物的可能性。 2。描述膜联蛋白II和Mekk4之间的相互作用。我们的数据表明膜联蛋白II和MEKK4之间的相互作用，导致MEKK4活动。由于MEKK4似乎在膜联蛋白II的下游起作用，因此这些蛋白质之间的生化关联将映射到特定的域。 3。表征PAI-1和PAI-2的砷依赖性调节。我们建议，由膜联蛋白II和MEKK4调控的ERK MAP激酶信号通路可能是砷依赖性PAI表达调节的机制。 4。评估膜联蛋白II的特定功能。我们将创建一个特定于组织的基因敲除鼠标，有选择地破坏 平滑肌细胞中的膜联蛋白II表达，以评估整个动物中的砷毒性。 拟议的研究将进一步了解砷诱导的信号传导过程的重要性及其对外周血管系统的不利影响并促进组织损伤。