Cholesterol Homeostasis in the Retina

视网膜中的胆固醇稳态

• 批准号: 10161784
• 负责人: Irina A Pikuleva
• 金额: $ 44.38万
• 依托单位: CASE WESTERN RESERVE UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2007
• 资助国家: 美国
• 起止时间: 2007-09-01 至 2025-03-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10161784
• 关键词: Ablation; Affect; Age related macular degeneration; Aging; Anabolism; Animal Model; Apolipoprotein E; Apolipoproteins; Blindness; Blood Circulation; Bruch' s basal membrane structure; Cell membrane; Cellular Membrane; Cholesterol; Cholesterol Homeostasis; Clinical Trials; Cytochrome P450; Data; Development; Disease; Dose; Drug Delivery Systems; Drug Prescriptions; Drug vehicle; Drusen; Elderly; Enzymes; Equilibrium; Evaluation; Eye diseases; FDA approved; Genes; Genetic; Genetic study; Grant; Hamsters; High Density Lipoproteins; Human; In Situ; Industrialization; Knowledge; Lead; Link; Lipids; Lipoproteins; Location; Low-Density Lipoproteins; Maintenance; Measures; Mediating; Membrane; Mesocricetus auratus; Metabolism; Modeling; Mus; Output; Pathogenesis; Pathway interactions; Patients; Phagocytosis; Pharmaceutical Preparations; Pharmacologic Substance; Pharmacological Treatment; Pharmacology; Photoreceptors; Plasma; Process; Proteins; Research; Retina; Risk; Risk Factors; Rodent; Role; Side; Simvastatin; Source; Structure of retinal pigment epithelium; Study models; Testing; Transgenic Organisms; apolipoprotein D; beta-Cyclodextrins; cholesterol biosynthesis; cholesterol trafficking; combat; density; insight; mouse model; novel therapeutics; particle; prospective; subcutaneous; sulfated glycoprotein 2; uptake

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.

胆固醇在视网膜中是丰富的，视网膜通过平衡胆固醇代谢途径来维持胆固醇稳态。 胆固醇的输入和输出。视网膜胆固醇输入包括局部生物合成和从全身吸收。 流通视网膜胆固醇输出通过光感受器吞噬作用实现，通过光感受器吞噬作用代谢为氧固醇。 细胞色素P450酶，并通过脂蛋白转运到体循环。机制复杂 控制和协调视网膜胆固醇输入和输出，以维持脂质稳态水平。积累 数据表明视网膜胆固醇稳态异常与年龄相关性黄斑变性的发病机制有关 (AMD)这是工业化国家老年人视力丧失的主要原因。胆固醇的细节- 然而，由于对视网膜胆固醇维持的认识不足，AMD的联系仍然不清楚。期间 在前一个资助期，我们确定了：1）视网膜胆固醇生物合成的相对贡献， 全身胆固醇摄取占总视网膜胆固醇输入; 2）胆固醇转运的视网膜意义 以及3）不同药物治疗对降低视网膜胆固醇的作用。具体地说， 我们发现局部生物合成是小鼠视网膜胆固醇的主要来源， 由降胆固醇药物辛伐他汀抑制。此外，我们确定载脂蛋白E和D 对视网膜胆固醇转运很重要，这是一种也可以靶向视网膜的途径， 导致视网膜胆固醇降低。最后，我们发现，胆固醇过剩可以在视网膜酯化， 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 将继续描绘视网膜胆固醇维持的未知方面，这是毫无疑问的， 这对我们了解如何对抗AMD非常重要。目标1将评估仓鼠作为研究模型 视网膜胆固醇在啮齿类动物中，就整体而言，仓鼠比小鼠更接近人类。 身体胆固醇维持。因此，我们将研究使用仓鼠是否有任何优势， 建立视网膜胆固醇稳态的细节以及药物治疗。目标2和3 仍将使用小鼠，因为根据这些目的进行的研究不应受到以下潜在种间差异的影响： 视网膜胆固醇维持。目标2将集中在2-羟丙基-b-环糊精，FDA批准的 针对胆固醇分布的药物。这种胆固醇相关的药理学潜力 降低视网膜胆固醇的方法尚未研究，将在几只小鼠上进行试验 模型目的3建立载脂蛋白J在视网膜胆固醇代谢途径中的意义 运输几种载脂蛋白似乎是视网膜中胆固醇运输所必需的，包括 载脂蛋白J是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 与胆固醇在视网膜和布鲁赫膜中的有害积累有关。