Insulin, a new role in retinal homeostasis and disease

胰岛素在视网膜稳态和疾病中的新作用

• 批准号: 9911635
• 负责人: Jon Iker Etchegaray
• 金额: $ 6.93万
• 依托单位: UNIVERSITY OF VIRGINIA
• 依托单位国家: 美国
• 财政年份: 2020
• 资助国家: 美国
• 起止时间: 2020-02-01 至 2022-01-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9911635
• 关键词: Age related macular degeneration; Alleles; Alzheimer' s Disease; Apoptotic; Atrophic; Biology; Blindness; Blood; Blood Circulation; Blood Glucose; Blood Vessels; Blood flow; Blood-Retinal Barrier; Body part; Cell membrane; Cells; Complex; Consumption; Cues; Development; Diabetic Retinopathy; Disease; Electroretinography; Energy Supply; Ensure; Equilibrium; Event; Excision; Eye; Eye diseases; Failure; Fenestrated Capillary; Functional disorder; Glucose; Glucose Transporter; Growth; Homeostasis; Hormones; Human body; Impairment; Insulin; Ions; Knock-out; Lead; Light; Liver; LoxP-flanked allele; Measures; Mediating; Metabolic; Metabolic Control; Metabolism; Mus; Muscle function; Na(+)-K(+)-Exchanging ATPase; Neuraxis; Neurons; Nutritional; Nutritional status; Optical Coherence Tomography; Organ; Oxidative Phosphorylation; Oxidative Stress; Pancreas; Pathology; Phagocytosis; Photoreceptors; Pigments; Play; Process; Production; Recycling; Research; Retina; Retinal Degeneration; Retinitis Pigmentosa; Role; SLC2A1 gene; Signal Transduction; Source; Structure of retinal pigment epithelium; Testing; Time; Tissues; Up-Regulation; Vascular blood supply; Vision; Visual; Waste Products; aerobic glycolysis; aminoacid biosynthesis; apical membrane; basolateral membrane; capillary bed; cost; food consumption; fundus imaging; glucose metabolism; glucose transport; glucose uptake; insulin secretion; insulin signaling; monolayer; neovascularization; novel therapeutics; photoreceptor degeneration; tool; visual cycle

Abstract Different organs within our bodies have different energy requirements. Such requirements are influenced by the particular function performed by the organ, and the body’s nutritional status. Moreover, energy use of one organ is many times matched by a decrease in energy consumption of another. The liver, for example, will decrease, and sometimes spend energy to support muscle function. However, the central nervous system (CNS) needs to utilize adequate amounts of energy, irrespective of the body’s nutritional status or the metabolic needs of other organs. How the CNS is able to obtain this “metabolic privilege” is unclear, yet deficits in energy supply to the CNS often underlie diseases such as age-related macular degeneration (AMD) and Alzheimer’s disease. Insulin is the major anabolic hormone in the body. Primarily produced in the pancreas, insulin is released into the blood upon the consumption of food. When sensed by cells in other parts of the body, insulin triggers a cascade of signaling events that allow tissues to take up glucose from circulation. In the context of the retina, insulin is important in homeostasis. Absence of insulin can lead to eye specific diseases such as diabetic retinopathy. Yet how insulin regulates glucose metabolism in the retina is unclear. Crucial to glucose and overall retinal metabolism is the retinal pigment epithelium (RPE). The RPE is a monolayer of pigmented cells forming the blood retinal barrier and recent research has shown that the RPE regulates glucose transport from the periphery into the retina. Preliminary studies in our lab have uncovered that the RPE mediates insulin signaling in the retina. The purpose of this proposal therefore is to test the importance of RPE mediated insulin signaling on glucose metabolism within the retina. We hypothesize that insulin, through the RPE, allows the eyes to maintain an adequate supply of energy at all times, irrespective of nutritional status. Furthermore, we hypothesize that failure in insulin signaling coming from this source can lead to problems in visual function, including neovascularization and photoreceptor atrophy. To test this we will first measure what triggers RPE mediated insulin signaling. We will then measure the impact that knocking out insulin has on glucose uptake by the retina. Finally, we will analyze the downstream consequences that impaired RPE mediated insulin signaling has on retina homeostasis and disease. The results of these studies could provide exciting new concepts on the biology of the eye itself, energy utilization in the retina, and help develop new therapeutics to treat blindness.

抽象的 我们体内的不同器官具有不同的能量需求。这样的要求受 器官执行的特定功能以及人体的营养状况。此外，能量使用一个 器官多次与另一个人的能源消耗减少相匹配。例如，肝脏将 减少，有时花费能量来支持肌肉功能。但是，中枢神经系统 （CNS）需要利用足够的能量，无论人体的营养状况如何 其他器官的代谢需求。中枢神经系统如何获得这种“代谢特权”尚不清楚，但缺陷 在向中枢神经系统的能源供应中，通常是疾病的基础，例如与年龄相关的黄斑变性（AMD）和 阿尔茨海默氏病。 胰岛素是体内主要的合成代谢马。胰岛素主要在胰腺中产生，释放到 食物消费时的血液。当细胞在人体其他部位感测时，胰岛素会触发A 一系列信号事件，使组织可以从循环中吸收葡萄糖。在视网膜的背景下 胰岛素在稳态中很重要。缺乏胰岛素会导致眼睛特异性疾病，例如糖尿病 视网膜病。然而，胰岛素如何调节视网膜中的葡萄糖代谢尚不清楚。对葡萄糖至关重要 总体残留代谢是视网膜色素上皮（RPE）。 RPE是色素细胞的单层 形成血液残留障碍和最近的研究表明，RPE调节来自 进入视网膜的外围。我们实验室的初步研究发现了RPE介导胰岛素 在视网膜中发出信号。因此，该建议的目的是测试RPE介导的胰岛素的重要性 对视网膜内葡萄糖代谢的信号传导。我们假设胰岛素通过RPE允许 无论营养状况如何，眼睛始终保持足够的能量供应。此外，我们 假设来自此源的胰岛素信号传导失败会导致视觉功能的问题， 包括新血管形成和感光细胞萎缩。为了测试这一点，我们将首先测量什么触发RPE 介导的胰岛素信号传导。然后，我们将测量胰岛素对葡萄糖摄取的影响 视网膜。最后，我们将分析RPE介导的胰岛素信号转导的下游后果 患有视网膜体内稳态和疾病。这些研究的结果可能会提供令人兴奋的新概念 眼睛本身的生物学，视网膜中的能量利用，并有助于开发新的疗法以治疗 失明。