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: 10672366
• 负责人: Rithwick Rajagopal
• 金额: $ 38.88万
• 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/10672366
• 关键词: ATF6 gene; Ablation; Acceleration; Acetyl-CoA Carboxylase; Address; Adenosine Monophosphate; Adult; Affect; Agonist; Agreement; 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; 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.

项目摘要 糖尿病性视网膜病是视力障碍和失明的日益普遍原因 成年人。现代疗法已经变得越来越有效，但仍然不足以防止视力丧失 相当比例的患者。需要早期行动和高效的新疗法，尤其是因为 全球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。在此应用程序中，我们将通过早期研究来解决此障碍 糖尿病期间残留代谢的变化 - 可能导致疾病发作的变化，并且 可以针对治疗目的。 高血糖是所有形式的糖尿病的标志，与其并发症直接相关， 包括糖尿病性视网膜病。由于葡萄糖是视网膜的主要燃料，我们研究了什么病理 由于其糖尿病的过量供应可能会发生影响。具体来说，我们发现糖尿病是相关的 永久性代谢的根本转移远离组织分解（分解代谢）和组织 建筑物（代谢）。最大的变化之一是脂质生物合成，这是一种负责 在棕榈酸盐的哺乳动物细胞中产生无处不在的中链脂肪酸。在糖尿病中，视网膜棕榈酸酯 与非糖尿病对照相比，合成升高70％。使用针对性的遗传操纵 合成途径中的酶，我们确定棕榈酸酯的减少可防止糖尿病的视力丧失 而提升生产则加速了视觉异常的发作。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。达到这些目标，我们 最近发现，糖尿病性视网膜中超过棕榈酸酯会影响受调节的几种视网膜酶 通过s-甲米二酰化。在视网膜ryanodine受体2（RYR2）中看到了最大的变化 - 细胞内离子 调节钙稳态的渠道 - 因为它在糖尿病中是超甲米的，与非糖尿病相比 控件。在此应用中，我们将确定这种分子变化是否与病理和 是否可以逆转治疗作用。 我们将解决三个主要目的：（1）定义糖尿病对残留Ryr2棕榈酰化及其的影响 功能后果； （2）描述杆中与RyR2相关的钙通量是否取决于残留 脂质生物发生； （3）确定改善糖尿病中残留的脂肪生成信号传导是否会减少糖尿病 视网膜病的严重程度。通过完成这些目标，我们可以发现糖尿病的基本根本原因 视网膜病变，我们可能会引入针对这种疾病早期阶段的新型治疗目标 过程。