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Sexual hormones, cardiac mast cells and cardioprotection

性激素、心脏肥大细胞和心脏保护

基本信息

批准号：
7249503
负责人：
Joseph S Janicki
金额：
$ 37.84万
依托单位：
UNIVERSITY OF SOUTH CAROLINA AT COLUMBIA
依托单位国家：
美国
项目类别：
财政年份：
2004
资助国家：
美国
起止时间：
2004-07-01 至 2010-06-30
项目状态：
已结题

项目摘要

DESCRIPTION (provided by applicant): While cardiovascular disease is the leading cause of death in both men and women in the United States, it is only after menopause that the risk of developing congestive heart failure dramatically increases in women. The proposed study will investigate gender-specific differences in myocardial remodeling and the development of heart failure secondary to chronic volume overload. Specifically, the focus of this proposal will be estrogen's modulation of TNF-alpha production and release from cardiac mast cells. The overall hypothesis to be examined is that estrogen modulation of TNF-alpha is responsible for the gender differences in cardiovascular remodeling induced by chronic volume overload. To this end, the following specific aims will be addressed using a variety of physiological, biochemical, morphological and molecular techniques to delineate the mechanisms responsible for the gender-specific differences in cardiovascular function and the temporal progression of adverse ventricular remodeling induced secondary to either infrarenal aortocaval fistula or TNF-alpha infusion in rats. Aim 1: Does estrogen alter the dynamic remodeling process induced by chronic volume overload? Aim 2: What role does the estrogen modulation of TNF-alpha play in myocardial remodeling and development of heart failure? Aim 3: Is estrogen modulation of mast cell-derived TNF-alpha the mechanism responsible for cardioprotection observed in intact females? In summary, the proposed studies will provide a well integrated approach designed to fill a void in our understanding of the mechanisms responsible for the cardioprotection observed in premenopausal females. We have every expectation that the investigations will significantly increase our understanding of the important interactions between estrogen, cardiac mast cell-derived TNF-alpha, cardiac fibroblasts, myocytes, and the extracellular matrix during cardiovascular remodeling secondary to chronic volume overload and advance the development of novel therapeutic approaches for the prevention of heart failure.

描述（由申请人提供）：虽然心血管疾病是美国男性和女性死亡的主要原因，但只有在绝经后，女性患充血性心力衰竭的风险才显著增加。该研究将调查心肌重塑和继发于慢性容量超负荷的心力衰竭发展的性别特异性差异。具体地说，这项建议的重点将是雌激素的调节TNF-α的生产和释放从心脏肥大细胞。待检验的总体假设是，雌激素对TNF-α的调节是慢性容量超负荷诱导的心血管重塑的性别差异的原因。为此，将使用各种生理学、生物化学、形态学和分子学技术来阐明以下具体目标，以描述导致心血管功能性别特异性差异的机制，以及继发于肾下下腔静脉瘘或TNF-α输注的大鼠不良心室重塑的时间进展。目的1：雌激素是否改变慢性容量超负荷引起的动态重构过程？目的2：雌激素对TNF-α的调节在心肌重塑和心力衰竭的发生中起什么作用？目的3：雌激素对肥大细胞源性TNF-α的调节是否是在完整女性中观察到的心脏保护机制？总之，拟议的研究将提供一个很好的综合方法，旨在填补我们对绝经前女性中观察到的心脏保护机制的理解空白。我们完全期望这些研究将显著增加我们对雌激素、心脏肥大细胞源性TNF-α、心脏成纤维细胞、肌细胞和细胞外基质在慢性容量超负荷继发心血管重塑过程中的重要相互作用的理解，并促进预防心力衰竭的新治疗方法的开发。