SIGNALING MECHANISMS GOVERNING CARDIAC HYPERTROPHY

描述：（改编自研究者摘要）压力超负荷 诱发的心脏肥大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是 不清楚PI已经表明，阻断应激激活的 通过腺病毒介导的显性蛋白激酶基因转移， 抑制性突变体SEK-1（KR）消除了 体外培养心肌细胞。最重要的是，PI发现基因转移 SEK-1（KR）对大鼠心肌的压力超负荷有明显的抑制作用 心脏肥大，这表明SAPKs对肥大的 体内反应。本提案的目的是确定 SAPK通路和一种以前不知道在细胞凋亡中起作用的信号通路， 肥大反应，糖原合成酶激酶-3（GSK-3）途径，在 体内心脏肥大的发展。具体目标包括：1. 确定SAPK通路在压力超负荷发展中的作用 体内心脏肥大。初步数据表明， 对压力超负荷肥大的发展至关重要。他们将 完成了这些研究，这些研究使用SEK-1（KR）在大鼠心脏中的基因转移， 阻断压力超负荷肥大。2.确定GSK-3在 心肌细胞肥大反应。很明显， 信号通路肥大，可以部分弥补损失， SAPK信号。其中之一可能是钙调神经磷酸酶/NF-AT 3通路。 该通路在T细胞中受GSK-3负调控，但GSK-3的作用是抑制T细胞的增殖。 是心肌细胞放大肥大细胞的重要机制， 反应3.确定GSK-3活性的调节是否改变了 体内肥大反应。他们将使用腺病毒介导的基因转移 的组成性活性或显性阴性GSK-3 β，以确定作用 压力超负荷性肥大的途径。这些研究将提供 更好地了解体内调节肥大的途径， 确定那些可能成为新治疗策略靶点的途径 以防止患者的心脏肥大。

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.