Cholesterol Homeostasis in the Retina

视网膜中含有丰富的胆固醇，它通过平衡下列途径来维持胆固醇的稳态 胆固醇的输入和输出。视网膜胆固醇的输入包括局部生物合成和来自全身的摄取 发行量。视网膜胆固醇的输出是通过光感受器的吞噬作用实现的，代谢为氧甾醇是通过 细胞色素P450酶，并通过脂蛋白运输到体循环。精心设计的机制 控制和协调视网膜胆固醇的输入和输出，以维持血脂的稳定水平。积累 视网膜胆固醇代谢紊乱在老年性黄斑变性发病机制中的作用 老年性黄斑变性(AMD)是工业化国家老年人视力丧失的主要原因。关于胆固醇的细节- 然而，由于对视网膜胆固醇维持的了解不足，AMD之间的联系仍然不清楚。在.期间 在之前的授权期内，我们确定：1)视网膜胆固醇生物合成和 全身性胆固醇对视网膜总胆固醇输入的摄取；2)胆固醇转运的视网膜意义 和储存；3)不同药物治疗对降低视网膜胆固醇的影响。具体来说， 我们发现，局部生物合成是小鼠视网膜胆固醇的主要来源，也是一种途径，可以 被降胆固醇药物辛伐他汀抑制。此外，我们建立了载脂蛋白E和D 对视网膜胆固醇的运输很重要，这一途径也可以作为药理学的靶点 导致视网膜胆固醇降低。最后，我们发现过量的胆固醇可以在视网膜中酯化。 并形成脂滴，即确定了一种管理视网膜胆固醇超载的机制。在这次更新中，我们 将继续描述视网膜胆固醇维持的未知方面，这些方面是毫无疑问的 对于我们了解如何抗击AMD很重要。目标1将评估仓鼠作为研究的模型 视网膜胆固醇。在啮齿动物中，仓鼠比老鼠的整体更接近人类 身体胆固醇的维持。因此，我们将调查使用仓鼠来 建立视网膜胆固醇动态平衡的细节以及药物治疗。目标2和目标3 将仍然使用小鼠，因为在这些目标下的研究不应该受到潜在的物种间差异的影响 视网膜胆固醇的维持。AIM 2将专注于FDA批准的2-羟丙基-b-环糊精 针对胆固醇分布的药物。这种胆固醇相关物质的药理潜力 降低视网膜胆固醇的过程尚未被研究，将在几只小鼠身上进行测试 模特们。目的3将确定载脂蛋白J在视网膜胆固醇途径中的意义 运输。几种载脂蛋白似乎是胆固醇在视网膜中运输所必需的，包括 载脂蛋白J，一种具有独特功能的蛋白质。总的来说，这三个目标将主要提供新的 关于视网膜中胆固醇的信息，并促进疾病新疗法的开发 与视网膜和Bruchs膜中有害的胆固醇积聚有关。

Cholesterol is abundant in the retina, which maintains cholesterol homeostasis by balancing the pathways of cholesterol input and output. Retinal cholesterol input includes local biosynthesis and uptake from the systemic circulation. Retinal cholesterol output is realized via photoreceptor phagocytosis, metabolism to oxysterols by cytochrome P450 enzymes, and transport to the systemic circulation by lipoproteins. Elaborate mechanisms control and coordinate retinal cholesterol input and output to maintain lipid steady-state levels. Accumulating data implicate retinal cholesterol dyshomeostasis in the pathogenesis of age-related macular degeneration (AMD), the leading cause of vision loss in the elderly of the industrialized world. The details of the cholesterol- AMD link are, however, still unclear, due to insufficient knowledge about retinal cholesterol maintenance. During the previous grant period, we ascertained: 1) the relative contributions of retinal cholesterol biosynthesis and uptake of systemic cholesterol to the total retinal cholesterol input; 2) retinal significance of cholesterol transport and storage; and 3) the effect of different pharmacologic treatments on lowering retinal cholesterol. Specifically, we found that local biosynthesis is the major source of retinal cholesterol in mice, and a pathway, which can be inhibited by a cholesterol lowering drug simvastatin. Furthermore, we established that apolipoproteins E and D are important for retinal cholesterol transport, a pathway which could be targeted pharmacologically as well and lead to retinal cholesterol lowering. Finally, we discovered that cholesterol excess could be esterified in the retina and form lipid droplets, i.e., identified a mechanism for managing retinal cholesterol overload. In this renewal we will continue to delineate the unknown aspects of retinal cholesterol maintenance that are of unquestionable importance for our understanding of how to combat AMD. Aim 1 will evaluate hamsters as a model for studies of retinal cholesterol. Among rodents, hamsters are much closer to humans than mice in terms of their whole body cholesterol maintenance. Hence, we will investigate whether there is any advantage in using hamsters for establishing the details of retinal cholesterol homeostasis as well as pharmacologic treatments. Aims 2 and 3 will still use mice as studies under these Aims should not be affected by potential interspecies differences in retinal cholesterol maintenance. Aim 2 will focus on 2-hydroxypropyl-b-cyclodextrin, the FDA-approved pharmaceutical that targets cholesterol distribution. The pharmacologic potential of this cholesterol-related process for retinal cholesterol lowering has not yet been investigated and will be tested on several mouse models. Aim 3 will establish retinal significance of apolipoprotein J for the pathway of retinal cholesterol transport. Several apolipoproteins appear to be necessary for cholesterol trafficking in the retina, including apolipoprotein J, a protein with unique functions. Collectively, the three Aims will provide principally new information about cholesterol in the retina and facilitate the development of new therapeutics for the diseases associated with deleterious accumulations of cholesterol in the retina and Bruch’s membrane.