Modulating retinal lipid biogenesis in diabetes for therapeutic effects

调节糖尿病视网膜脂质生物合成以获得治疗效果

• 批准号: 10503919
• 负责人: Rithwick Rajagopal
• 金额: $ 38.23万
• 依托单位: WASHINGTON UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2022
• 资助国家: 美国
• 起止时间: 2022-08-01 至 2027-06-30
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10503919
• 关键词: ATF6 gene; Ablation; Acetyl-CoA Carboxylase; Address; Adenosine Monophosphate; Adult; Affect; Agonist; Anabolism; Biogenesis; Blindness; Calcium; Catabolism; Cells; Cellular Stress; Clinical; Data; Development; Diabetes Mellitus; Diabetic Retinopathy; Disease; Endoplasmic Reticulum; Enzymes; Fatty-acid synthase; Glucose; Goals; Health; Homeostasis; Human; Hyperglycemia; Image; Injury; Ion Channel; Link; Lipids; Mammalian Cell; Mass Spectrum Analysis; Medium chain fatty acid; Metabolic; Metabolism; Metformin; Modeling; Modernization; Modification; Molecular; Onset of illness; Palmitates; Palmitic Acids; Pathogenesis; Pathologic; Pathology; Pathway interactions; Patients; Pattern; Phosphotransferases; Photoreceptors; Plant Roots; Post-Translational Protein Processing; Prevalence; Process; Production; Proteins; Public Health; Reporting; Retina; Retinal Diseases; Rod; Ryanodine Receptor Calcium Release Channel; Severities; Signal Transduction; Signaling Molecule; Stress; Testing; Therapeutic Effect; Tissues; Transgenic Organisms; Vision; Visual; Visual impairment; calcium indicator; cost; diabetic; disability; endoplasmic reticulum stress; experimental study; gain of function; genetic manipulation; improved; inhibitor; lipid biosynthesis; lipid metabolism; new therapeutic target; non-diabetic; novel; palmitoylation; prevent; public health relevance; release of sequestered calcium ion into cytoplasm; retinal rods; targeted treatment; therapy development; visual cycle

Project Summary Diabetic retinopathy is an increasingly common cause of visual impairment and blindness among adults. Modern therapy has become increasingly effective, but remains insufficient to prevent vision loss in a sizable proportion of patients. Early-acting and efficacious new remedies are needed, especially since the prevalence of worldwide disease is increasing. A barrier to accomplishing this goal is a poor understanding of the earliest causes of retinal injury in diabetes. In this application, we will address this barrier by studying early changes in retinal metabolism during diabetes – changes that are likely to contribute to disease onset and that can be targeted for therapeutic purposes. Hyperglycemia is the hallmark of all forms of diabetes and is directly related to its complications, including diabetic retinopathy. Since glucose is the primary fuel of the retina, we investigated what pathological effects might occur due to its excess supply in diabetes. Specifically, we discovered that diabetes is associated with a fundamental shift in retinal metabolism away from tissue break down (catabolism) and towards tissue building (anabolism). Among the largest changes is that of lipid biosynthesis, a pathway responsible for generating a ubiquitous medium-chain fatty acid in mammalian cells, palmitate. In diabetes, retinal palmitate synthesis is elevated by 70% compared to non-diabetic controls. Using targeted genetic manipulation of the enzymes in the synthesis pathway, we determined that reduction of palmitate prevents vision loss in diabetes whereas elevating its production accelerates the onset of visual abnormalities. We now ask how such signals are related to disease development and what specific molecules are involved. Towards these goals, we recently found that excess palmitate in the diabetic retina impacts several retinal enzymes that are regulated by S-palmitoylation. The largest change was seen in retinal Ryanodine Receptor 2 (Ryr2) – an intracellular ion channel that regulates calcium homeostasis – as it is hyper-palmitoylated in diabetes compared to non-diabetic controls. In this application we will determine whether this molecular change is associated with pathology and whether it can be reversed for therapeutic effects. We will address three major aims: (1) define the effect of diabetes on retinal Ryr2 palmitoylation and its functional consequences; (2) delineate whether Ryr2-associated calcium flux in rods is dependent on retinal lipid biogenesis; and (3) determine whether improving retinal lipogenic signaling in diabetes reduces diabetic retinopathy severity. By accomplishing these aims, we could uncover essential root causes of diabetic retinopathy and we may introduce novel targets for therapy directed at a very early stage of the disease process.

项目概要 糖尿病视网膜病变是导致视力障碍和失明的一个日益常见的原因 成年人。现代疗法已变得越来越有效，但仍不足以预防视力丧失 患者比例相当大。需要尽早采取有效的新疗法，特别是因为 世界范围内疾病的患病率正在增加。实现这一目标的障碍是对 糖尿病视网膜损伤的最早原因。在这个应用程序中，我们将通过早期学习来解决这个障碍 糖尿病期间视网膜代谢的变化——可能导致疾病发作的变化 可以靶向治疗目的。 高血糖是所有形式糖尿病的标志，与其并发症直接相关， 包括糖尿病视网膜病变。由于葡萄糖是视网膜的主要燃料，我们研究了什么是病理性的 由于其在糖尿病中的供应过多，可能会产生影响。具体来说，我们发现糖尿病与 视网膜代谢发生根本性转变，从组织分解（分解代谢）转向组织分解 建设（合成代谢）。其中最大的变化是脂质生物合成，这是负责 产生哺乳动物细胞中普遍存在的中链脂肪酸棕榈酸酯。在糖尿病中，视网膜棕榈酸酯 与非糖尿病对照组相比，合成增加了 70%。使用有针对性的基因操作 合成途径中的酶，我们确定减少棕榈酸酯可以预防糖尿病患者的视力丧失 而提高其产量会加速视觉异常的发生。我们现在问这样的信号如何 与疾病的发展以及涉及哪些特定分子有关。为了实现这些目标，我们 最近发现，糖尿病视网膜中过量的棕榈酸会影响几种受调节的视网膜酶 通过S-棕榈酰化。最大的变化出现在视网膜 Ryanodine 受体 2 (Ryr2)——一种细胞内离子 调节钙稳态的通道——与非糖尿病患者相比，糖尿病患者的钙离子高度棕榈酰化 控制。在此应用中，我们将确定这种分子变化是否与病理学相关，以及 是否可以逆转以达到治疗效果。 我们将实现三个主要目标：(1) 定义糖尿病对视网膜 Ryr2 棕榈酰化及其影响 功能性后果； (2) 描绘视杆细胞中与 Ryr2 相关的钙通量是否依赖于视网膜 脂质生物发生； (3) 确定改善糖尿病患者的视网膜脂肪生成信号是否可以减少糖尿病的发生 视网膜病变的严重程度。通过实现这些目标，我们可以发现糖尿病的根本原因 视网膜病变，我们可能会在疾病的早期阶段引入新的治疗靶点 过程。