RAMP3 Modulation of GPER1 Function in Cardiovascular Disease

RAMP3 对心血管疾病中 GPER1 功能的调节

• 批准号: 8224241
• 负责人: Patricia Marie Lenhart-Pendergrass
• 金额: $ 2.92万
• 依托单位: UNIV OF NORTH CAROLINA CHAPEL HILL
• 依托单位国家: 美国
• 财政年份: 2010
• 资助国家: 美国
• 起止时间: 2010-08-30 至 2015-08-29
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8224241
• 关键词: Affect; Age; Agonist; American; Angiotensin II; Binding; Breeding; COS-7 Cell; Cardiac; Cardiovascular Diseases; Cardiovascular system; Cause of Death; Cell membrane; Cells; Cessation of life; Development; Disease Progression; Disease susceptibility; Estrogens; Family; Family member; Female; G-Protein-Coupled Receptors; Gender; Genetic; Genetic Models; Genotype; Goals; Health; Heart; Heart Diseases; Heart Hypertrophy; Heart failure; Human; In Vitro; Lead; Ligands; Mediating; Menopause; Mus; Mutate; N-ethylmaleimide-sensitive protein; Nature; Pathway interactions; Phenotype; Play; Proteins; RAMP3; Recycling; Research Proposals; Risk; Role; Signal Pathway; Signal Transduction; Specificity; Testing; Therapeutic; Transfection; United States; Woman; disease phenotype; improved; in vivo; interest; male; men; mouse model; new therapeutic target; novel; public health relevance; receptor; receptor recycling; receptor-activity-modifying protein; sex; trafficking

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.

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性差异可能是雌激素介导的，但调节雌激素心脏保护作用的遗传途径尚未阐明。受体活性修饰蛋白（RAMP）是跨膜辅助蛋白，已知其与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。RAMP 3是独特的，因为它是由雌激素和CVD转录诱导。此外，与其他RAMP家族成员不同，已知RAMP 3能够通过与NSF的PDZ基序依赖性缔合来改变GPCR再循环至质膜。GPER 1是一种新的心脏保护性雌激素结合GPCR，在女性和CVD中的水平增加。我们的初步研究结果表明，RAMP 3的遗传缺失导致GPER 1在心肌细胞质膜上的水平以性别依赖的方式降低，这为RAMP 3与GPER 1的相互作用提供了证据。我们将使用转染的细胞在体外研究RAMP 3和GPER 1之间的潜在相互作用，以确定RAMP 3是否可以改变GPER 1再循环到质膜。此外，我们将进行体内研究，以确定GPER 1信号的药理学激活是否影响RAMP 3-/-雄性和雌性小鼠在心力衰竭遗传背景下的心血管表型。该提案的结果将阐明RAMP 3和GPER 1在性别依赖性心脏保护中的作用，并有可能为性别定制的CVD治疗确定新的治疗靶点。 公共卫生相关性： 叙述性心脏病是一种常见的健康状况，是美国男性和女性死亡的主要原因，每年造成超过630，000人死亡。这意味着美国每四个死亡中就有一个是由于心脏病。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，它对两性的影响不同。在更年期之前，女性通常不会患心脏病，而同龄男性相比之下风险更高。然而，绝经后，女性患心脏病的风险急剧增加。心脏病易感性和进展的性别依赖性差异可能是由雌激素介导的，但调节这种效应的遗传途径尚未明确确定。在这项研究中，我们将研究可能涉及心脏病性别依赖性差异的特定信号通路。由于心脏病是对美国人健康的普遍和严重威胁，这些研究对于阐明这种疾病发展和进展的机制非常重要，其总体目标是改善人类健康。