SR-BI AND MACROPHAGE CHOLESTEROL METABOLISM

描述（改编自研究者摘要）： 本提案中需要审查的是SR-B1必须与caveolae相关， 促进选择性胆固醇酯摄取和游离胆固醇流出， 巨噬细胞目的1：确定SR-131需要小窝的程度 以促进巨噬细胞中胆固醇酯的摄取和胆固醇流出。 我们已经建立了仅表达SR-131或SR-BI和小窝蛋白的细胞系。 因此，我们可以研究SR-131介导的摄取和流出的能力。 脂质在存在或不存在小窝。我们将在2015年确认我们的发现。 人原代单核细胞衍生的巨噬细胞。目标2：确定 氧化脂蛋白改变小窝结构，抑制SR BI依赖性 巨噬细胞中的胆固醇流量。这将通过评估i） 氧化脂蛋白对小窝脂质组成的影响，ii） 氧化脂蛋白对小窝结构的影响，iii） 小窝修饰对SR-131亚细胞定位的影响， 和iv）氧化脂蛋白对SR-131活性的影响。目标3： 确定SR-B1的巨噬细胞特异性过表达的影响， 小窝蛋白对转基因小鼠动脉粥样硬化病变发展的影响。这 将通过使用过表达SR-131，小窝蛋白， 或通过巨唾液酸蛋白启动子在巨噬细胞中两者。将小鼠 与动脉粥样硬化易感apoE -/-菌株杂交， 动脉粥样硬化量化的病变的大小，并通过 胆固醇/胆固醇酯含量的病变。

DESCRIPTION (Adapted from Investigator's Abstract): The central hypothesis to be examined in this proposal is that SR-B1 must be associated with caveolae to promote selective cholesterol ester uptake and free cholesterol efflux from macrophages. Aim 1: To determine the extent to which SR-131 requires caveolae to facilitate cholesterol ester uptake and cholesterol efflux in macrophages. We have established cell lines that express only SR-131 or SR-BI and caveolin. Therefore, we can study the ability of SR-131 to mediated uptake and efflux of lipid in the presence or absence of caveolae. We will confirm our findings in human primary monocyte-derived macrophages. Aim 2: To determine the extent to which oxidized lipoproteins alter caveola structure and inhibit SR BI-dependent cholesterol flux in macrophages. This will be accomplished by assessing i) the effects of oxidized lipoproteins on the lipid composition of caveolae, ii) the effects of oxidized lipoproteins on the structure of caveolae, iii) the influence of caveolae modifications on the subcellular localization of SR-131, and iv) the effects of oxidized lipoproteins on SR-131 activity. Aim 3: To determine the effect of macrophage-specific over-expression of SR-B1 and caveolin on the development of atherosclerotic lesions in transgenic mice. This will be investigated by using transgenic mice over-expressing SR-131, caveolin, or both in macrophages by means of the macrosialin promoter. The mice will be crossbred to the atherosclerosis susceptible apoE -/- strain and the extent of atherosclerosis quantified by the size of the lesion and by the cholesterol/cholesterol ester content of the lesions.