SIGNALING MECHANISMS GOVERNING CARDIAC HYPERTROPHY

描述：(改编自《调查者摘要》)压力过载 诱导性心肌肥厚是心力衰竭的常见原因。尽管如此， 在体内介导肥大发展的信号通路有 不清楚。PI已经表明，阻断激活的应力激活 蛋白激酶(SAPKs)经腺病毒介导的显性基因转移 抑制性突变体SEK-1(KR)可抑制血管肥大反应 体外培养心肌细胞。最重要的是，私家侦探发现基因转移 SEK-1(KR)对大鼠心肌压力超负荷的抑制作用 心肌肥厚，提示SAPKs在心肌肥厚中起关键作用 体内反应。这项提案的目标是确定 SAPK通路和以前未知的信号通路在 肥大反应，糖原合成酶激酶-3(GSK-3)途径，在 活体心肌肥大的发生。具体目标包括：1. 确定SAPK通路在压力超负荷形成中的作用 活体心肌肥大。初步数据显示，SAPK是 对压力超负荷性肥大的发展至关重要。他们会 完成这些利用大鼠心脏中SEK-1(KR)基因转移的研究 阻滞性压力超负荷肥大。2.确定GSK-3在 心肌细胞肥大反应。很明显，有多余的 信号通路肥大，可以部分补偿丢失的 SAPK信令。其中之一可能是钙调神经磷酸酶/核因子-AT3途径。 这一途径在T细胞中受到GSK-3的负调控，但GSK-3的作用 是心肌细胞放大肥大的重要机制 回应。3.确定GSK-3活性的调制是否改变了 体内肥大反应。他们将使用腺病毒介导的基因转移 构成活性或显性阴性的GSK-3β来确定其作用 在压力超负荷性肥厚的通路中。这些研究将为 更好地了解体内调节肥厚的途径，并 确定那些可能成为新治疗策略靶点的途径 预防患者心肌肥厚。

DESCRIPTION: (Adapted from the Investigator's Abstract) Pressure overload induced cardiac hypertrophy is a common cause of heart failure. Despite this, the signaling pathways which mediate the development of hypertrophy in vivo are unclear. The PI has shown that blocking activation of the stress-activated protein kinases (SAPKs) by adenovirus mediated gene transfer of a dominant inhibitory mutant, SEK-1(KR), abrogated the hypertrophic response of cardiomyocytes in vitro. Most importantly, the PI has found that gene transfer of SEK-1(KR) to rat myocardium significantly inhibited pressure overload cardiac hypertrophy, suggesting that the SAPKs are critical to the hypertrophic response in vivo. The goal of this proposal is to determine the role of the SAPK pathway and a signaling pathway previously not known to play a role in the hypertrophic response, the glycogen synthase kinase-3 (GSK-3) pathway, in the development of cardiac hypertrophy in vivo. The Specific Aims include: 1. Determine the role of the SAPK pathway in the development of pressure overload cardiac hypertrophy in vivo. The preliminary data suggest that the SAPKs are critical to the development of pressure overload hypertrophy. They will complete these studies which use gene transfer of SEK-1(KR) in rat heart to block pressure overload hypertrophy. 2. Determine the role of GSK-3 in the hypertrophic response of cardiomyocytes. It is clear that there are redundant pathways signaling hypertrophy which can, in part, compensate for the loss of SAPK signaling. One of these is likely to be the calcineurin/NF-AT3 pathway. This pathway is negatively regulated by GSK-3 in T cells, but the role of GSK-3 is an important mechanism whereby cardiomyocytes amplify the hypertrophic response. 3. Determine whether modulation of GSK-3 activity alters the hypertrophic response in vivo. They will use adenovirus-mediated gene transfer of constitutively active or dominant negative GSK-3 beta to determine the role of the pathway in pressure overload hypertrophy. These studies will provide for better understanding of the pathways regulating hypertrophy in vivo, and to identify those pathways which could be targets for novel therapeutic strategies to prevent cardiac hypertrophy in patients.