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依赖差异可能是雌激素介导的，但调节雌激素心脏保护的遗传途径尚未被阐明。受体活性修饰蛋白（RAMPs）是一种跨膜辅助蛋白，已知与g蛋白偶联受体（gpcr）相互作用，并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转录诱导的。此外，与其他RAMP家族成员不同，RAMP3以其通过与NSF的PDZ基序依赖关联改变GPCR再循环到质膜的能力而闻名。GPER1是一种新型的保护心脏的雌激素结合GPCR，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的遗传缺失导致心脏细胞质膜上GPER1水平以性别依赖的方式降低，这为RAMP3与GPER1的相互作用提供了证据。我们将在体外利用转染细胞研究RAMP3和GPER1之间潜在的相互作用，以确定RAMP3是否可以改变GPER1向质膜的再循环。此外，我们将进行体内研究，以确定GPER1信号的药理激活是否会影响具有心力衰竭遗传背景的RAMP3-/-雄性和雌性小鼠的心血管表型。这项研究的结果将阐明RAMP3和GPER1在性别依赖性心脏保护中的作用，并有可能为CVD的性别定制治疗确定新的治疗靶点。

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.