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The conditional GPR30 knockout mouse: a model of female-specific cardiac aging

条件性 GPR30 基因敲除小鼠：女性特异性心脏衰老模型

基本信息

批准号：
8443711
负责人：
LEANNE GROBAN
金额：
$ 7.4万
依托单位：
WAKE FOREST UNIVERSITY HEALTH SCIENCES
依托单位国家：
美国
项目类别：
财政年份：
2012
资助国家：
美国
起止时间：
2012-09-15 至 2014-08-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8443711
关键词：
Ablation Address Adult Adverse effects Affect Age Aging Agonist Animal Model Attenuated Bilateral oophorectomy Biological Preservation Blood Pressure Breeding Cardiac Cardiac Myocytes Cardiology Cardiovascular Diseases Cause of Death Cell membrane Chronic Coupled Data Development Diastolic heart failure Disease Doxycycline Elements Endoplasmic Reticulum Estrogen Receptor alpha Estrogen Receptors Estrogens Exercise Exercise Tolerance Experimental Models Extracellular Matrix Female Fibroblasts Fibrosis Functional disorder G-Protein-Coupled Receptors GTP-Binding Proteins Gene Deletion Gene Expression Gene Expression Profile Genes Goals Heart Heart Diseases Heart Hypertrophy Heart failure Hormone replacement therapy Hypertension Impairment Infarction Intervention Knock-out Knockout Mice Knowledge Lead Left Left Ventricular Hypertrophy Left Ventricular Remodeling Left ventricular structure Life Maintenance Menopause Methodology Modeling Molecular Mus Muscle Cells Myocardial Myocardium Ovarian hormone Phenotype Physiological Play Positioning Attribute Postmenopause Premenopause Prevalence Prevention therapy Procedures Rat-1 Relaxation Reperfusion Injury Research Research Methodology Research Personnel Research Project Grants Research Proposals Resistance Risk Factors Rodent Rodent Model Role Sodium Chloride Stress Structure Technology Testing Therapeutic Time Tissues Uncertainty Ventricular Ventricular Remodeling Wild Type Mouse Woman Women&apos s Health Work age related aged base blood glucose regulation cardiovascular disorder prevention constriction expectation experience functional disability hemodynamics hypertensive heart disease improved in vivo knockout gene mRNA Expression mouse model novel novel therapeutics older women preclinical study pressure prevent protective effect protein expression research study response salt intake sex stressor systolic hypertension therapeutic target young adult

项目摘要

DESCRIPTION (provided by applicant): The prevalence of diastolic dysfunction sharply increases in women after menopause and may lead to heart failure, for which there are no proven treatments. While evidence suggests that estrogen may protect the premenopausal heart from hypertension and ventricular remodeling, the mechanisms involved are not understood. The newly recognized G protein-coupled estrogen receptor, GPR30, may protect postmenopausal women from cardiovascular disease. However, appropriate animal models need to be established and refined to better understand how activation of cardiac GPR30 might reduce the likelihood of diastolic dysfunction and its progression to diastolic heart failure in oler women. The primary objective of this pilot research study is two-fold: first, to generate and characterize the cardiomyocyte-specific, doxycycline-inducible GPR30 knockout mouse and second, to determine the molecular, histological, and functional roles of GPR30 in hearts from adult female mice exposed to chronic hemodynamic overload induced by transverse aortic constriction. To attain this objective, we will test the working hypothesis thatin the absence of cardiac GPR30, impairments in myocardial relaxation, left ventricular chamber compliance, exercise tolerance and left ventricular remodeling are accelerated compared to age-matched GPR30-intact littermates exposed to the same perturbation. We will test our hypothesis utilizing a new rodent model that involves the Cre/loxP gene knockout methodology, coupled with non-invasive and invasive in vivo assessments of cardiac function, structure and hemodynamics in the female cardiomyocyte-specific, doxycycline-inducible GPR30 knockout mouse. The ability to spatially (cardiac tissue only) and temporally regulate GPR30 gene expression is critical when establishing experimental models that mimic the dynamic ovarian hormone milieu of aging women. Successful completion of the proposed research will contribute a missing, fundamental element to our existing knowledge, without which we cannot understand the cardio-specific role of GPR30 inactivation in accelerated cardiac aging of postmenopausal women. This knowledge will be important in testing GPR30-related molecular mechanisms behind the development and progression of sex-specific diastolic dysfunction, and to test new therapeutic strategies. When the proposed studies have been completed, it is our expectation that 1) we will fully characterize the molecular, histological, ad functional cardiac phenotype of the cardiomyocyte-specific, doxycycline-inducible GPR30 knockout mouse, and 2) we will identify, in our unique model, whether the unfavorable structural and functional features (specifically, diastolic dysfunction, reduced exercise capacity, and left ventricular remodeling) of deleting GPR30 in female mice are initiated and/or exacerbated by experimentally-induced pressure overload. Such a finding would allow development of much-needed therapeutic approaches, such as GPR30 activation, to be temporally initiated to prevent the progression of accelerated cardiac aging, or diastolic dysfunction, after menopause or the onset of systolic hypertension. PUBLIC HEALTH RELEVANCE: Diastolic dysfunction is prevalent among older women and antedates heart failure, for which there is no proven treatment. These studies will test the use of a new mouse model to define the cardiac-specific role of the novel G protein-coupled estrogen receptor, GPR30, in the female heart. The proposed project could lead to much-needed improved pharmacological interventions for cardiac disease prevention and therapy in aging women.

描述（由申请人提供）：绝经后女性舒张功能障碍的患病率急剧增加，并可能导致心力衰竭，目前尚无有效的治疗方法。虽然有证据表明雌激素可以保护绝经前心脏免受高血压和心室重塑的影响，但其机制尚不清楚。新发现的G蛋白偶联雌激素受体GPR 30可能保护绝经后妇女免于心血管疾病。然而，需要建立和完善适当的动物模型，以更好地了解心脏GPR 30的激活如何降低心脏舒张功能障碍的可能性及其进展为舒张性心力衰竭。这项试点研究的主要目的有两个：首先，产生和表征心肌细胞特异性的、多西环素诱导的GPR 30敲除小鼠，其次，确定GPR 30在暴露于由横向主动脉收缩诱导的慢性血液动力学超负荷的成年雌性小鼠心脏中的分子、组织学和功能作用。为了达到这一目的，我们将检验工作假设，即与暴露于相同扰动的年龄匹配的GPR 30完整的同窝仔相比，心脏GPR 30缺失时，心肌舒张、左心室腔顺应性、运动耐量和左心室重构的损伤加速。我们将测试我们的假设，利用一个新的啮齿类动物模型，涉及Cre/loxP基因敲除方法，再加上非侵入性和侵入性的心脏功能，结构和血流动力学在女性心肌细胞特异性，强力霉素诱导GPR 30敲除小鼠体内评估。在建立模拟老年妇女动态卵巢激素环境的实验模型时，空间（仅心脏组织）和时间调节GPR 30基因表达的能力至关重要。成功完成拟议的研究将为我们现有的知识提供一个缺失的基本要素，没有它，我们就无法理解GPR 30失活在绝经后妇女心脏加速老化中的心脏特异性作用。这些知识对于检测性别特异性舒张功能障碍发展和进展背后的GPR 30相关分子机制以及测试新的治疗策略将是重要的。当所提出的研究已经完成时，我们的期望是：1）我们将充分表征心肌细胞特异性的、多西环素诱导的GPR 30敲除小鼠的分子、组织学和功能心脏表型，以及2）我们将在我们独特的模型中鉴定不利的结构和功能特征是否在雌性小鼠中，缺失GPR 30的心脏舒张功能障碍（具体地，舒张功能障碍、运动能力降低和左心室重塑）是由实验诱导的压力超负荷引发和/或加剧的。这一发现将允许开发急需的治疗方法，如GPR 30激活，暂时启动，以防止绝经后或收缩期高血压发作后加速心脏衰老或舒张功能障碍的进展。公共卫生相关性：舒张功能障碍在老年妇女中普遍存在，并先于心力衰竭，目前尚无有效的治疗方法。这些研究将测试使用一种新的小鼠模型，以确定女性心脏中新型G蛋白偶联雌激素受体GPR 30的心脏特异性作用。拟议的项目可能导致急需改进的药物干预，用于老年妇女心脏病的预防和治疗。