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

临床和基础科学研究表明，核因子-kappaB(NF-kappaB)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。尽管我们已经证明，核因子-kappaB在心脏I/R后的整体作用是损伤的，但核因子-kappaB能够激活细胞生存/生长因子和与心脏保护和抗凋亡作用相关的基因，以及与炎症和凋亡细胞死亡相关的基因。然而，对于不同的、可能重叠的依赖于核因子-kappaB的基因如何调节对立的病理生理过程，人们知之甚少。本研究的目的是阐明核因子-kappaB参与缺血/再灌注损伤的机制，以及晚期缺血PC的心脏保护作用。中心假说是，核因子-kappaB是包括细胞因子和丝裂原活化蛋白激酶(MAPK)在内的多种信号通路的关键整合因子，并通过调节依赖于核因子-kappaB的基因来影响细胞在I/R后和晚期PC发育过程中的死亡/存活。这一假说建立在以下初步结果的基础上：基因阻断NF-kappaB影响I/R损伤，并通过调节iNOS、COX2、HSP70和金属硫蛋白等关键基因来消除晚期PC对MI的保护作用。这项建议的具体目标是： 目的1.探讨核因子-kappaB依赖的基因表达在I/R损伤和晚期缺血PC中的作用。 目的2.阐明激活核因子-kappaB的信号通路，以及I/R后和晚期PC后发生的关键的串扰相互作用。 目的3.确定核因子-kappaB影响基因表达的转录机制 缺血再灌注后细胞死亡和晚期缺血PC所致的心脏保护。 这一建议是创新的，因为它解决了一个新的概念：核因子-kappaB作为信号整合器或“枢纽”，通过对依赖于核因子-kappaB的基因的整合调节来影响心脏病理生理。这项研究的预期贡献是获得关于依赖于NF-kappaB的基因表达介导I/R损伤和唤起晚期PC的心脏保护作用的机制的新知识。这一点意义重大，因为机制上的理解对于制定阻断NF-kappaB和特定的一组依赖于NF-kappaB的基因的策略是必要的，以便开发新的治疗方案，使其最大限度地发挥有益作用，同时限制NF-kappaB信号的有害影响。

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.