Defining the role of DHHC3 in cardiac stress signaling

项目摘要 心力衰竭仍然是心血管疾病和死亡的重要因素，预计它将 患病率继续上升。进一步认识心脏致病的分子机制 失败将促进治疗这种疾病的新疗法的发展。蛋白质的脂类修饰 在它们的功能和定位方面都扮演着重要的角色。大量的心脏信号分子需要 脂化修饰，包括小的GTP酶和异源三聚体G蛋白。事实上，分子机制 他汀类药物治疗心肌肥厚部分归因于阻止Rho膜定位 通过阻断戊烯基化来抑制GTP酶。Rho GTP酶也是S-棕榈酰化的，但与戊烯基化不同，S-棕榈酰化 是一种可逆的脂质修饰，它控制GTP酶与质膜和它们的动态结合 活动。S-棕榈酰化是由新近发现的棕榈酰转移酶家族(PATS)执行的， 它含有一个保守的锌指结构域，如天冬氨酸-组氨酸-组氨酸-胱氨酸(ZDHHC)结构域 蛋白质家族被命名为。概述的提案试图阐明DHHC蛋白是如何构成心脏的 信号转导，更具体地说，高尔基体定位DHHC3(Godz)蛋白是如何引起病理的。 实验室的初步数据显示，Godz基因在小鼠心脏中的过度表达会导致心脏充血 衰竭之前心脏中RhoGTP酶的棕榈酰化、表达和活性增强。RhoGTP酶 在病理性肥厚背后的心脏应激信号中具有已知的作用。这导致我们假设 Godz代表了一种新的应激诱导的心脏病理信号的介体。两个具体目标是 建议检查Godz的心功能。目标1：研究Godz介导的机制 细胞内信号促进转基因小鼠心脏疾病的发生。目标2：确定生理相关性 Godz功能在病理性肥厚中的作用。总之，这些研究将大大增加我们的知识 心脏中棕榈酰化依赖的信号通路的研究，可能是一种新的治疗靶点 心脏病的治疗。

Project Summary Heart failure remains a significant contributor to both cardiovascular disease and death and it is predicted to continue to increase in prevalence. A further understanding of the molecular mechanisms contributing to heart failure will serve to catalyze development of novel therapeutics to treat this disease. Lipid modification of proteins plays important roles in both their function and localization. Numerous cardiac signaling molecules require lipidation modification, including small GTPases and heterotrimeric G-proteins. In fact, the molecular mechanism of statins in treating cardiac hypertrophy is partially attributed to preventing membrane localization of Rho GTPases by blocking prenylation. Rho GTPases are also S-palmitoylated but unlike prenylation, S-palmitoylation is a reversible lipid modification that controls dynamic GTPase association with the plasma membrane and their activity. S-palmitoylation is executed by the recently discovered family of palmitoyl acyltransferases (PATs), which contain a conserved zinc finger like aspartate-histidine-histidine-cystine (zDHHC) domain for which the family of proteins are named. The outlined proposal seeks to elucidate how DHHC proteins underlie cardiac signal transduction, and more specifically, how the Golgi localized DHHC3 (Godz) protein causes pathology. Preliminary data from the lab showed that cardiac overexpression of Godz in mice results in congestive heart failure preceded by enhanced palmitoylation, expression, and activity of RhoGTPase in heart. RhoGTPases have known roles in cardiac stress signaling underlying pathological hypertrophy. This led us to hypothesize that Godz represents a novel mediator of stress induced pathological signaling in the heart. Two specific aims are proposed to examine Godz in cardiac function. Aim 1: Examine mechanisms whereby Godz-mediated intracellular signaling promotes disease in hearts of transgenic mice. Aim 2: Determine the physiologic relevance of Godz function in pathological hypertrophy. Together, these studies will substantially increase our knowledge of palmitoylation dependent signaling pathways in heart which may represent a novel therapeutic target for treatment of heart disease.