Establishing basic biological mechanisms governing cardiovascular benefits

建立控制心血管益处的基本生物学机制

• 批准号: 298450-2010
• 负责人: Moghadasian, Mohammed
• 金额: $ 2.19万
• 依托单位: University of Manitoba
• 依托单位国家: 加拿大
• 项目类别: Discovery Grants Program - Individual
• 财政年份: 2013
• 资助国家: 加拿大
• 起止时间: 2013-01-01 至 2014-12-31
• 项目状态: 已结题
• 来源: https://www.nserc-crsng.gc.ca/ase-oro/Details-Detailles_eng.asp?id=526038
• 关键词: Establishing; basic; biological; mechanisms; governing

The previous NSERC Discovery Grant allowed us to learn potential synergistic effects of dietary agents and anti-rejection drugs in a rat heart transplant model. Thus, in the proposed studies we want to utilize our experiences to further enhance our knowledge of basic mechanisms of the development and prevention of transplant coronary atherosclerosis usin a genetically modified mouse model. The following 3 aims will be included in these studies:Aim 1: Cardiovascular benefits including prevention of post heart transplant complications of dietary phytosterols and nitrites are medicated through alterations in immune system. We will perform heart transplant surgeries in mice. After a full recovery from surgery, the mice will be treated with experimental diets containing phytosterols alone or with nitrite or with probucol for 12 weeks. Both dietary phytosterols and nitrite are supposed to produce anti-inflammatory conditions and probucol will produce pro-inflammatory conditions. The state of inflammation will be studied by 4 distinct but interrelated methods including, estimation of plasma cytokine levels, response of spleen cells to a number of stimulants, investigation of inflammation-related gene expression in white blood cells, and finally identification of inflammatory cells and markers in atherosclerotic lesions using immunohistochemistry techniques. Aim 2: Cardiovascular benefits of dietary phytosterols and nitrite may be mediated through alterations in the coagulation system. We will feed these mice with the above mentioned diets for 6 months. A number of coagulatory factors and their gene expression will be studied and correlated with the extent and severity of atherosclerosis. Aim 3: Dietary phytosterols and nitrite preserve cardiac function and rhythm through an overall prevention of coronary atherogenesis. Our knowledge on the impact of coronary atherosclerosis on heart function is limited. Thus we will feed these mice with above-mentioned diets for 1 year to develop advanced heart disease. The mice will undergo echocardiography procedures to evaluate heart function every 8 weeks. At sacrifice the aorta will be examined using the novel and a sophisticated image analysis method.

之前的 NSERC 发现补助金使我们能够了解饮食药物和抗排斥药物在大鼠心脏移植模型中的潜在协同效应。因此，在拟议的研究中，我们希望利用我们的经验，进一步增强我们对使用转基因小鼠模型进行移植冠状动脉粥样硬化的发展和预防的基本机制的了解。这些研究将包括以下 3 个目标： 目标 1：通过改变免疫系统来治疗心血管益处，包括预防膳食植物甾醇和亚硝酸盐的心脏移植后并发症。我们将对小鼠进行心脏移植手术。从手术中完全康复后，小鼠将接受仅含有植物甾醇或亚硝酸盐或普罗布考的实验饮食治疗12周。膳食植物甾醇和亚硝酸盐都应该产生抗炎作用，而普罗布考会产生促炎作用。将通过 4 种不同但相互关联的方法来研究炎症状态，包括估计血浆细胞因子水平、脾细胞对多种兴奋剂的反应、白细胞中炎症相关基因表达的研究，以及最后使用免疫组织化学技术鉴定动脉粥样硬化病变中的炎症细胞和标记物。目标 2：膳食植物甾醇和亚硝酸盐对心血管的益处可能是通过改变凝血系统来介导的。我们将用上述饮食喂养这些小鼠 6 个月。将研究许多凝血因子及其基因表达，并将其与动脉粥样硬化的程度和严重程度相关联。目标 3：膳食植物甾醇和亚硝酸盐通过全面预防冠状动脉粥样硬化来保护心脏功能和节律。我们对冠状动脉粥样硬化对心脏功能影响的了解有限。因此，我们将用上述饮食喂养这些小鼠一年，使其发展为晚期心脏病。小鼠将每 8 周接受一次超声心动图检查以评估心脏功能。牺牲时，将使用新颖且复杂的图像分析方法对主动脉进行检查。