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 糖尿病视网膜病变是一个越来越常见的原因，视力损害和失明， 成年人了现代治疗已变得越来越有效，但仍不足以防止视力丧失， 相当大比例的患者。需要早期有效的新疗法，特别是因为 世界范围内疾病的流行率正在增加。实现这一目标的一个障碍是对 糖尿病视网膜损伤的最早原因。在本申请中，我们将通过早期研究来解决这一障碍。 糖尿病期间视网膜代谢的变化-可能导致疾病发作的变化， 可以用于治疗目的。 高血压是所有形式糖尿病的标志，并与其并发症直接相关， 包括糖尿病性视网膜病变。由于葡萄糖是视网膜的主要燃料，我们研究了视网膜的病理变化。 糖尿病患者可能因其过量供应而产生影响。具体来说，我们发现糖尿病与 随着视网膜代谢从组织分解（catalysis）向组织分解（catalysis）的根本转变， 建筑物（Ancestor）。其中最大的变化是脂质生物合成，这是一种负责 在哺乳动物细胞中产生一种普遍存在的中链脂肪酸，棕榈酸。在糖尿病中， 与非糖尿病对照相比，合成提高了70%。使用有针对性的基因操作， 通过研究合成途径中的酶，我们确定棕榈酸的减少可以预防糖尿病患者的视力丧失 而增加其产量则会加速视觉异常的发生。我们现在要问的是， 与疾病的发展和参与的特定分子有关。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。视网膜Ryanodine受体2（Ryr 2）的变化最大， 调节钙稳态的通道-因为与非糖尿病患者相比，糖尿病患者的棕榈酰化程度较高 对照在本申请中，我们将确定这种分子变化是否与病理学相关， 是否可以逆转治疗效果。 我们将解决三个主要目标：（1）确定糖尿病对视网膜Ryr 2棕榈酰化的影响， （2）描述视杆细胞中Ryr 2相关的钙流是否依赖于视网膜神经节细胞的生长。 脂质生物生成;和（3）确定改善糖尿病中视网膜脂肪生成信号传导是否减少糖尿病性视网膜病变。 视网膜病变严重程度。通过实现这些目标，我们可以揭示糖尿病的根本原因。 我们可能会在疾病的早期阶段引入新的治疗靶点 过程