NF-kappaB Signaling Networks in I/R and Late PC

I/R 和晚期 PC 中的 NF-kappaB 信令网络

• 批准号: 6914998
• 负责人: Walter Keith Jones
• 金额: $ 38.38万
• 依托单位: UNIVERSITY OF CINCINNATI
• 依托单位国家: 美国
• 财政年份: 1999
• 资助国家: 美国
• 起止时间: 1999-07-01 至 2008-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6914998
• 关键词: apoptosis; biological signal transduction; cardiac myocytes; chromatin immunoprecipitation; cytokine; cytoprotection; gene expression; genetic regulation; genetic regulatory element; genetically modified animals; histopathology; intermolecular interaction; laboratory mouse; microarray technology; mitogen activated protein kinase; molecular pathology; myocardial ischemia /hypoxia; nitric oxide synthase; nuclear factor kappa beta; phosphorylation; posttranslational modifications; prostaglandin endoperoxide synthase; protein structure function; tumor necrosis factor alpha; western blottings

Clinical and basic science studies demonstrate that nuclear factor-kappaB (NF-kappaB) is activated after ischemia/reperfusion (I/R) and is positively correlated with increased morbidity and mortality in patients with unstable angina. Although we have shown that the overall effect of NF-kappaB in the heart after I/R is injurious, NF-kappaB is capable of activating cell-survival/growth factors and genes associated with cardioprotective and anti-apoptotic effects as well as genes associated with inflammation and apoptotic cell death. Yet there is little understanding of how antithetical pathophysiological processes are regulated by different and possibly overlapping sets of NF-kappaB-dependent genes. The goal of this proposal is to delineate the mechanisms by which NF-kappaB contributes to ischemia/reperfusion injury on one hand and the cardioprotective effects of late ischemic PC on the other. The central hypothesis is that NF-kappaB is a key integrator of multiple signaling pathways, including cytokines and mitogen-activated protein kinases (MAPK), and acts, via regulation of NF-kappaB-dependent genes, to influence cell death/survival after I/R and during development of late PC. This hypothesis is based upon Preliminary Results that genetic blockade of NF-kappaB affects I/R injury and abrogates the protective effects of late PC against MI in association with modulation of critical genes including iNOS, Cox2, HSP70 and metallothionein. The specific Aims of the proposal are: Aim 1. Determine the role of NF-kappaB-dependent gene expression in I/R injury and late ischemic PC. Aim 2. Delineate the signaling pathways that activate NF-kappaB and the key cross-talk interactions that occur post-I/R and after late ischemic PC. Aim 3. Determine the transcriptional mechanism by which NF-kappaB affects gene expression to evoke cell death after I/R and cardioprotection consequent to late ischemic PC. This proposal is innovative in that it addresses a novel concept; that NF-kappaB acts as a signaling integrator or "hub" that affects cardiac pathophysiology by the integrative regulation of NF-kappaB-dependent genes. The expected contribution of the research is attainment of new knowledge regarding the mechanism by which NF-kappaB-dependent gene expression mediates I/R injury and evokes the cardioprotective effects of late PC. This is significant because a mechanistic understanding is necessary to develop strategies to block NF-kappaB and specific sets of NF-kappaB-dependent genes for the development of novel therapeutic regimens that maximize the beneficial effects while limiting the deleterious effects of NF-kappaB signaling.

临床和基础科学研究表明，核因子-κ B（NF-κ B）在缺血/再灌注（I/R）后被激活，并与不稳定型心绞痛患者发病率和死亡率的增加呈正相关。虽然我们已经证明I/R后NF-κ B在心脏中的总体作用是有害的，但NF-κ B能够激活细胞存活/生长因子和与心脏保护和抗凋亡作用相关的基因以及与炎症和凋亡性细胞死亡相关的基因。然而，很少有人了解如何相互对立的病理生理过程是由不同的和可能重叠的NF-κ B依赖基因集的调节。该建议的目的是阐明NF-κ B一方面促进缺血/再灌注损伤的机制，另一方面是晚期缺血PC的心脏保护作用。核心假设是，NF-κ B是多种信号传导途径的关键整合者，包括细胞因子和促分裂原活化蛋白激酶（MAPK），并且通过调节NF-κ B依赖性基因来影响I/R后和晚期PC发展期间的细胞死亡/存活。这一假设是基于初步结果，即NF-κ B的基因阻断影响I/R损伤，并消除与关键基因包括iNOS、Cox 2、HSP 70和金属硫蛋白的调节相关的晚期PC对MI的保护作用。该提案的具体目标是： 目标1。确定NF-κ B依赖性基因表达在I/R损伤和晚期缺血性PC中的作用。 目标二。描述激活NF-kappaB的信号通路以及I/R后和晚期缺血性PC后发生的关键串扰相互作用。 目标3。确定NF-κ B影响基因表达的转录机制， 引起I/R后细胞死亡和晚期缺血性PC后的心脏保护。 这个提议是创新的，因为它解决了一个新的概念，即NF-κ B作为一个信号整合剂或“枢纽”，影响心脏病理生理的NF-κ B依赖基因的整合调节。该研究的预期贡献是获得关于NF-κ B依赖性基因表达介导I/R损伤并引起晚期PC的心脏保护作用的机制的新知识。这是重要的，因为机制的理解是必要的，以开发策略，以阻止NF-κ B和特定组的NF-κ B依赖性基因的开发新的治疗方案，最大限度地发挥有益的效果，同时限制NF-κ B信号的有害影响。