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.

胆固醇在视网膜中丰富，该视网膜通过平衡胆固醇的稳态平衡来维持胆固醇的稳态 胆固醇输入和输出。视网膜胆固醇输入包括局部生物合成和全身性吸收 视网膜胆固醇输出是通过感光吞噬作用，对氧蛋白质的代谢来实现的。 细胞色素P450酶，并通过脂蛋白转运到全身循环。精致的机制 控制和协调仍然胆固醇的输入和输出以保持脂质稳态水平。累积 数据暗示残留的胆固醇dyshomeostasis在与年龄相关的黄斑变性的发病机理中 （AMD），在工业化世界中，视力丧失的主要原因。胆固醇的细节 - 但是，由于对永久胆固醇维持的知识不足，AMD链接仍然不清楚。期间 我们确定了上一个赠款期：1）残留胆固醇生物合成和 全身胆固醇吸收视网膜胆固醇的总输入； 2）胆固醇转运的视网膜意义 和存储； 3）不同药物治疗对降低常规胆固醇的影响。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，也是一种可以是的途径 降低胆固醇的辛伐他汀抑制。此外，我们确定了载脂蛋白E和D 对于视网膜胆固醇运输至关重要，视网膜胆固醇运输也可以是靶向药物的途径 导致视网膜胆固醇降低。最后，我们发现在视网膜中可以酯化胆固醇超过 并形成脂质液滴，即确定了管理视网膜胆固醇超负荷的机制。在这个续约中我们 将继续描述视网膜胆固醇维护的未知方面 对于我们对如何对抗AMD的理解的重要性。 AIM 1将评估仓鼠作为研究模型 视网膜胆固醇。在啮齿动物中，仓鼠比小鼠的整体更接近人类 身体胆固醇维持。因此，我们将调查使用仓鼠是否有任何优势 建立永久胆固醇稳态和药物治疗的细节。目标2和3 仍将使用小鼠，因为这些目标下的研究不应受到潜在的种间差异的影响 视网膜胆固醇维持。 AIM 2将重点放在2-羟基丙基-B-Cyclodextrin，FDA批准的 靶向胆固醇分布的药物。该胆固醇相关的药物潜力 尚未研究视网膜胆固醇的过程，并将在几只小鼠上进行测试 型号。 AIM 3将建立载脂蛋白J对视网膜胆固醇途径的视网膜意义 运输。几种载脂蛋白似乎对于视网膜中的胆固醇贩运是必需的，包括 载脂蛋白J，一种具有独特功能的蛋白质。总体而言，这三个目标将主要提供新的 有关视网膜中胆固醇的信息，并维持开发新疾病疗法 与视网膜和Bruch膜中胆固醇的有害积累有关。