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一个重要因素， 患病率继续上升。对心脏病分子机制的进一步认识 失败将促进治疗这种疾病的新疗法的开发。蛋白质的脂质修饰 在其功能和定位上起着重要的作用。许多心脏信号分子需要 脂化修饰，包括小GTP酶和异源三聚体G蛋白。事实上， 他汀类药物治疗心肌肥厚的作用部分归因于阻止Rho的膜定位 通过阻断异戊烯化来抑制GTP酶。Rho GTP酶也是S-棕榈酰化的，但与异戊二烯化不同，S-棕榈酰化 是一种可逆的脂质修饰，其控制GTdR与质膜的动态结合， 活动S-棕榈酰化由最近发现的棕榈酰酰基转移酶（PAT）家族执行， 其含有保守的锌指样组氨酸-组氨酸-胱氨酸（zDHHC）结构域， 蛋白质家族被命名。概述的建议旨在阐明DHHC蛋白如何成为心脏的基础。 信号转导，更具体地，高尔基体定位的DHHC3（Godz）蛋白如何引起病理。 实验室的初步数据显示，小鼠心脏中Godz的过度表达导致充血性心脏病。 心脏中RhoGT3的棕榈酰化、表达和活性增强。RhoGTP酶 在病理性肥大的心脏应激信号传导中具有已知的作用。这让我们假设， Godz代表了心脏中应激诱导的病理信号传导的新介质。两个具体目标是 建议检查戈兹的心脏功能目的1：研究Godz介导的 细胞内信号传导促进转基因小鼠心脏的疾病。目的2：确定生理相关性 在病理性肥大中的作用。总之，这些研究将大大增加我们对 棕榈酰化依赖的信号通路，这可能是一个新的治疗靶点， 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.