RAMP3 Modulation of GPER1 Function in Cardiovascular Disease

描述(由申请人提供)：心血管疾病(CVD)易感性和进展的性别差异可能是由雌激素介导的，但调控雌激素心脏保护的遗传途径尚未阐明。受体活性修饰蛋白或RAMP是已知的与G蛋白偶联受体(GPCRs)相互作用的跨膜辅助蛋白，在受体运输和配体特异性中发挥作用。RAMP3的独特之处在于它是由雌激素和心血管疾病在转录水平上诱导的。此外，与其他RAMP家族成员不同的是，RAMP3以其通过与NSF的PDZ基序依赖的结合改变GPCR到质膜的循环的能力而闻名。GPER1是一种新型的心脏保护性雌激素结合GPCRs，在女性和心血管疾病中水平升高。我们的初步研究结果表明，RAMP3的基因缺失会导致心肌细胞质膜上GPER1水平的降低，这与性别有关，这为RAMP3与GPER1的相互作用提供了证据。我们将使用转基因细胞在体外研究RAMP3和GPER1之间的潜在相互作用，以确定RAMP3是否可以改变GPER1对质膜的循环。此外，我们还将进行体内研究，以确定在心力衰竭的遗传背景下，GPER1信号的药理激活是否会影响RAMP3-/-雄性和雌性小鼠的心血管表型。这项建议的结果将阐明RAMP3和GPER1在性别依赖性心脏保护中的作用，并有可能确定针对性别定制的心血管疾病治疗的新治疗靶点。 公共卫生相关性： 叙事心脏病是一种常见的健康状况，在美国是导致男性和女性死亡的主要原因，每年导致超过63万人死亡。这意味着美国每四例死亡中就有一例死于心脏病。虽然心脏病对男性和女性都有影响，但由于我们不完全了解的原因，它对两性的影响是不同的。在绝经前，女性通常不会患心脏病，而同龄男性的风险则更高。然而，绝经后，女性患心脏病的风险会急剧增加。心脏病易感性和进展的性别差异可能是由雌激素介导的，但调节这种影响的遗传途径尚未明确。在这项研究计划中，我们将研究特定的信号通路，这些信号通路可能涉及心脏病的性别差异。由于心脏病对美国人的健康是如此普遍和严重的威胁，这些研究对于阐明这种疾病的发展和进展的机制非常重要，总体目标是改善人类健康。

DESCRIPTION (provided by applicant): Sex-dependent differences in cardiovascular disease (CVD) susceptibility and progression may be estrogen-mediated, but the genetic pathways regulating estrogen cardioprotection have yet to be elucidated. Receptor Activity Modifying Proteins, or RAMPs, are transmembrane accessory proteins that are known to interact with G-protein coupled receptors (GPCRs) and play a role in receptor trafficking and ligand specificity. RAMP3 is unique in that it is transcriptionally induced by estrogen and CVD. Also, unlike other RAMP family members, RAMP3 is known for its ability to alter GPCR recycling to the plasma membrane through a PDZ motif-dependent association with NSF. GPER1 is a novel cardioprotective estrogen-binding GPCR that is present in increased levels in females and in CVD. Our preliminary findings have shown that genetic loss of RAMP3 leads to reduced levels of GPER1 at the plasma membrane of cardiac cells in a sex-dependent fashion, providing evidence for an interaction of RAMP3 with GPER1. We will investigate the potential interaction between RAMP3 and GPER1 in vitro using transfected cells to determine whether RAMP3 can alter GPER1 recycling to the plasma membrane. In addition we will perform in vivo studies to determine whether pharmacological activation of GPER1 signaling affects the cardiovascular phenotype of RAMP3-/- male and female mice on a genetic background of heart failure. Results from this proposal will elucidate the role of RAMP3 and GPER1 in sex-dependent cardioprotection and have the potential of identifying novel therapeutic targets for gender-tailored treatment of CVD. PUBLIC HEALTH RELEVANCE: Narrative Heart Disease is a common health condition that ranks as the leading cause of death for both men and women in the United States, causing over 630,000 deaths each year. This means that one out of every four deaths in the U.S. is due to heart disease. Though heart disease affects both men and women, for reasons we do not fully understand, it affects the two sexes differently. Prior to menopause, women are generally protected from heart disease while men of the same age are at increased risk in comparison. However, after menopause, a woman's risk of developing heart disease drastically increases. Sex-dependent differences in heart disease susceptibility and progression may be mediated by estrogen, but the genetic pathways that regulate this effect have not yet been clearly identified. In this research proposal we will investigate specific signaling pathways that may be involved in the sex-dependent differences of heart disease. Because heart disease is such a prevalent and serious threat to American health, these studies are important to clarify the mechanisms that underlie the development and progression of this condition, with the overall goal of improving human health.