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，并与不稳定心绞痛患者发病率和死亡率增加呈正相关。虽然我们已经证明NF-kappaB在I/R后的心脏中的总体作用是有害的，但NF-kappaB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，以及与炎症和凋亡细胞死亡相关的基因。然而，对于不同的、可能重叠的nf - kappab依赖性基因如何调控对立的病理生理过程，人们知之甚少。本研究的目的是阐明NF-kappaB对缺血/再灌注损伤的作用机制，以及缺血晚期PC的心脏保护作用。核心假设是NF-kappaB是多种信号通路的关键整合子，包括细胞因子和丝裂原活化蛋白激酶（MAPK），并通过调节NF-kappaB依赖基因，影响I/R后和晚期PC发展过程中的细胞死亡/存活。这一假设是基于初步结果，即NF-kappaB的遗传阻断与iNOS、Cox2、HSP70和金属硫蛋白等关键基因的调节有关，可影响I/R损伤，并消除晚期PC对MI的保护作用。建议的具体目的是：

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.