Signaling for cardioprotection against oxidative stress

描述（由申请方提供）：心脏具有对抗氧化应激诱导损伤的内源性保护机制。然而，导致预防和保护心肌损伤的细胞机制尚未确定。缺乏这些知识会干扰旨在预防和/或治疗心脏病的新治疗策略的开发。我的长期目标是确定信号转导机制，从而保护成年心肌细胞。本申请的目的是具体评价加塔-4在由肝细胞生长因子和内皮素-1诱导的细胞存活信号传导中的作用。本申请的中心假设是肝细胞生长因子和内皮素-1保护心肌细胞免受氧化应激诱导的细胞死亡，部分是通过激活加塔-4上调细胞存活基因。这一假设是基于强有力的初步数据制定的，这些数据表明肝细胞生长因子和内皮素-1保护心肌细胞免受氧化应激并激活加塔-4。这项研究的基本原理是，一旦获得了保护心肌细胞的机制的知识，它将导致可用于预防和/或治疗心脏病的新策略，从而降低与这种疾病相关的发病率和死亡率。我特别准备进行拟议的研究，因为我的实验室已经证明，肝细胞生长因子和内皮素-1保护成人心肌细胞免受氧化应激，也磷酸化加塔-4，因此许多技术和试剂已经可用。将对中心假设进行检验，并通过追求两个具体目标来实现本申请的目的：1）确定加塔-4激活的机制，和2）确定肝细胞生长因子和内皮素-1保护心肌细胞的共同机制。拟议的工作是创新的，因为它将联合收割机结合成人心肌细胞的细胞和动物模型。因此，我们期望加塔-4在心肌细胞保护的信号转导中发挥重要作用。这些结果将是重要的，因为它们有望为心脏病的预防和治疗干预提供新的药物。此外，预计这些结果将从根本上推动心肌细胞生物学领域的发展。

DESCRIPTION (provided by applicant): The heart has endogenous protective mechanisms against oxidative stress-induced damage. The cellular mechanisms that lead to the prevention and protection of myocardial damage, however, have not been defined. Lack of such knowledge interferes with the development of new therapeutic strategies that are designed to prevent and/or treat heart disease. My long-range goal is to identify the signal transduction mechanisms, leading to the protection of adult cardiac myocytes. The objective of this application is to evaluate specifically the role of GATA-4 in cell survival signaling induced by hepatocyte growth factor and endothelin-l. The central hypothesis of the application is that hepatocyte growth factor and endothelin-1 protect cardiac myocytes against oxidative stress-induced cell death, in part, by upregulating cell survival genes via the activation of GATA-4. The hypothesis has been formulated on the basis of strong preliminary data, which suggest that hepatocyte growth factor and endothelin-1 protect cardiac myocytes against oxidative stress and activate GATA-4. The rationale for the proposed research is that, once knowledge of the mechanisms that are responsible for the protection of cardiac myocytes has been obtained, it will lead to new strategies that can be used to prevent and/or treat heart disease, thereby reducing the morbidity and mortality that are associated with this condition. I am uniquely prepared to undertake the proposed research because my laboratory has demonstrated that hepatocyte growth factor and endothelin-1 protect adult cardiac myocytes against oxidative stress and also phosphorylate GATA-4, thus many of the techniques and reagents are already available. The central hypothesis will be tested and the objective of the application accomplished by pursuing two specific aims: 1) Determine the mechanism of GATA-4 activation, and 2) Determine the common mechanism by which hepatocyte growth factor and endothelin-1 protect cardiac myocytes. The proposed work is innovative, because it will combine cellular and animal models of adult cardiac myocytes. It is my expectation that GATA-4 plays an important role in signal transduction for cardiac myocyte protection. These results will be significant because they are expected to provide new agents for preventative and therapeutic interventions for heart disease. In addition, it is expected that the results will fundamentally advance the field of cardiac muscle cell biology.