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: 7072310
• 负责人: Walter Keith Jones
• 金额: $ 37.47万
• 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/7072310
• 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-KAPPAB（NF-kappab）在缺血/再灌注后激活（I/R），并且与不稳定的心绞痛患者的发病率和死亡率呈正相关。尽管我们已经表明，I/R后NF-kappab在心脏中的总体作用是有害的，但NF-kappab能够激活与心脏保护和抗凋亡效应以及与炎症和肿瘤细胞死亡相关的基因以及基因相关的细胞生存/生长因子和基因。然而，几乎没有什么了解对立的病理生理过程如何受到不同且可能重叠的NF-kappab依赖性基因的调节。该提案的目的是描述NF-kappab一方面有助于缺血/再灌注损伤的机制，以及晚期缺血性PC对另一方面的心脏保护作用。中心假设是NF-kappab是多个信号通路的关键集成剂，包括细胞因子和有丝分裂原激活的蛋白激酶（MAPK）（MAPK），以及通过调节NF-kappab依赖性基因的调节，以影响I/R和PC后期PC发育后的细胞死亡/生存。该假设是基于初步结果，即NF-kappab的遗传阻断会影响I/R损伤，并消除了晚期PC对MI的保护作用，并与包括Inos，Cox2，HSP70和金属硫蛋白在内的关键基因的调节有关。该提案的具体目的是： AIM 1。确定NF-kappab依赖性基因表达在I/R损伤和晚期缺血PC中的作用。 AIM 2。描述激活NF-kappab的信号通路以及在I/R之后以及晚期缺血性PC之后发生的关键交叉对话相互作用。 目标3。确定nF-kappab影响基因表达的转录机制 I/R和心脏保护后唤起细胞死亡，导致晚期缺血性PC。 该提议具有创新性，因为它解决了一个新颖的概念。 NF-kappab充当信号积分或“枢纽”，通过NF-kappab依赖性基因的整合调节影响心脏病理生理。这项研究的预期贡献是获得有关NF-KAPPAB依赖性基因表达介导I/R损伤并唤起PC后期PC的心脏保护作用的新知识的新知识。这很重要，因为对于制定阻止NF-kappab的策略和特定的NF-kappab依赖性基因，对于开发新型治疗方案的策略是必要的，从而最大程度地提高了有益效果，同时限制了NF-kappab信号的有害影响。