Iron and Diabetic Retinopathy

铁和糖尿病视网膜病变

• 批准号: 10077564
• 负责人: Jaya Pranava Gnana-Prakasam
• 金额: $ 36.74万
• 依托单位: SAINT LOUIS UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2020
• 资助国家: 美国
• 起止时间: 2020-01-01 至 2024-12-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10077564
• 关键词: 3' Untranslated Regions; Acetoacetates; Acetone; Address; Adult; Affect; Age; Anabolism; Animals; Antioxidants; Area; Biochemistry; Bioinformatics; Biology; Blindness; Blood; Blood Circulation; Blood Vessels; Cell Death; Cell Survival; Cells; Collaborations; Colon; DNA; DNA Repair; Data; Degenerative Disorder; Diabetes Mellitus; Diabetic Nephropathy; Diabetic Retinopathy; Diabetic mouse; Diet; Economic Burden; Energy Supply; Environment; Enzymes; Epigenetic Process; FOXO3A gene; Family; Fasting; Fatty Acids; Frequencies; Genetic; Genetic Models; Glucose; Goals; Hepatic; Histone Deacetylase; Histone Deacetylase Inhibitor; Homeostasis; Human; Hyperglycemia; Inflammasome; Inflammation; Inflammatory; Insulin Resistance; Interleukin-1 beta; Interleukin-18; Iron; Iron Chelating Agents; Iron Overload; Ketone Bodies; Ketones; Kidney; Knockout Mice; Knowledge; Link; Liver; Measures; Mediating; Medical Care Costs; Medicine; Metabolic; Metabolism; Mitochondria; Molecular Biology; Mus; N-Acetylcysteinamide; Nature; Nerve Degeneration; Neurons; Non-Insulin-Dependent Diabetes Mellitus; Nutrient; Ophthalmology; Oxidative Stress; Oxidoreductase; Physiological; Prevalence; Production; Public Health; Reaction; Regulation; Reporting; Research; Response Elements; Retina; Retinal Degeneration; Retinal Neovascularization; Risk Factors; Role; Saints; Serum iron level result; Severities; Signal Pathway; Signal Transduction; Testing; Therapeutic; Tissues; Training; Transferase; Universities; Untranslated Regions; Urine; Vision; Work; base; beta-Hydroxybutyrate; cell type; diabetes management; diabetic; experience; experimental study; ganglion cell; glycemic control; improved; in vitro Assay; inhibitor/antagonist; insight; ketogentic; marenostrin; mouse model; new therapeutic target; novel; novel therapeutics; public health relevance; retinal neuron; screening; senior faculty; side effect; supportive environment; uptake

We reported recently that human and mouse diabetic retina have increased iron accumulation, and inducing diabetes in a genetic mouse model of systemic iron overload resulted in accelerated progression of diabetic retinopathy (DR). Iron, although an essential nutrient, when accumulated excessively leads to tissue damage. However, systemic administration of iron chelators is not a feasible therapeutic option to reduce tissue iron levels due to potential side effects of lowering serum iron levels. New mechanistic insights into the role of iron in ketone body synthesis and utilization is a critical gap in knowledge addressed in this application facilitating new therapeutic targets for DR. During conditions of prolonged fasting and diabetes, body utilizes fatty acids to make ketone bodies as an alternate metabolic fuel. β- hydroxybutyrate (β-OHB), acetoacetate and acetone, the three ketones produced in the body, are metabolically important because their accumulation in blood can cause ketoacidosis and secondly, depending on the physiological state, ketones supply energy for cell survival. The central hypothesis of this proposal is that retinal iron accumulation during DR inhibits endogenous ketone β- OHB production, activating NLRP3 inflammasome signaling and thereby accelerating cell death. We will test our hypothesis using three distinct conceptual, computational and experimental strategies. In aim 1, we will explore how cellular iron accumulation modulates endogenous ketone body synthesis. Liver, colon and retina synthesize most of the endogenous ketones. Here, we propose to determine the effect of iron on the function of the mitochondrial enzyme Bdh1, which catalyzes the final reaction for producing β-OHB, the principal ketone in circulation using 2 novel mouse lines, constitutive and RPE-specific Bdh1 knockout mice. In aim 2, we will examine the mechanisms by which iron-associated decrease in ketone body β-OHB impacts inflammation during DR. Our lab and others have reported that retinal iron increases NLRP3 inflammasome. A report in Nature Medicine showed that exogenous β-OHB, but not the ketone acetoacetate, reduces NLRP3 inflammasome. Here we propose to investigate if iron associated reduction in endogenous β-OHB synthesis augments inflammation through histone deacetylase-Foxo3a signaling. In aim 3, we will explore the effect of iron on the uptake of hepatic/RPE produced β-OHB by the neuronal cells, which are primarily dependent on ketone bodies during conditions of low glucose availability. We previously reported that monocarboxylate transporter SMCT1, the only known β-OHB transporter in ganglion cells, is downregulated during iron overload in retina. We will analyze the epigenetic mechanisms by which iron alters cellular uptake of β-OHB in neuronal cells causing cell death. The three proposed aims are supported by the past 10 years of training in iron homeostasis, a vibrant research environment at SLU, and continuing professional guidance and collaboration with senior faculty. Successful completion of this project will advance our understanding of how iron alters ketone metabolism and drive the field into new and underexplored areas, like metabolic reprogramming for efficient ketone body utilization.

我们最近报道，人类和小鼠糖尿病视网膜增加了铁的积累，并诱导 全身铁超负荷的遗传小鼠模型中的糖尿病导致糖尿病进展加速 视网膜病（DR）。铁虽然是一种必需营养素，但积累过多会导致组织损伤。 然而，全身施用铁螯合剂并不是降低组织铁水平的可行治疗选择 由于降低血清铁水平的潜在副作用，对铁在酮中的作用有了新的机制认识。 身体合成和利用是本申请中解决的知识中的一个关键差距，促进新的 DR 的治疗目标 在长期禁食和糖尿病的情况下，身体会利用脂肪酸来制造 酮体作为替代代谢燃料，包括 β-羟基丁酸 (β-OHB)、乙酰乙酸和丙酮，这三种物质。 体内产生的酮对代谢很重要，因为它们在血液中的积累会导致 其次，根据生理状态，酮为细胞生存提供能量。 该提议的中心假设是 DR 期间视网膜铁的积累抑制内源性酮 β- OHB 的产生、激活 NLRP3 炎性体信号传导并加速细胞死亡我们将进行测试。 我们的假设使用三种不同的概念、计算和实验策略。 探索细胞铁积累如何调节内源性酮体合成。 在这里，我们建议确定铁对功能的影响。 线粒体酶 Bdh1，催化最终反应生成 β-OHB，β-OHB 是体内的主要酮 使用 2 个新型小鼠品系（组成型小鼠和 RPE 特异性 Bdh1 敲除小鼠）进行循环 在目标 2 中，我们将。 检查与铁相关的酮体 β-OHB 减少影响炎症的机制 DR. 我们的实验室和其他人在《自然》杂志上报道了视网膜铁会增加 NLRP3 炎症小体。 医学表明，外源性 β-OHB（而不是乙酰乙酸酮）可以减少 NLRP3 炎症小体。 我们建议研究铁相关的内源性 β-OHB 合成减少是否会加剧炎症 通过组蛋白脱乙酰酶-Foxo3a 信号传导 在目标 3 中，我们将探讨铁对摄取的影响。 肝/RPE通过神经元细胞产生β-OHB，其主要依赖于酮体 我们之前报道过单羧酸转运蛋白 SMCT1，是唯一的葡萄糖可用性条件。 神经节细胞中已知的 β-OHB 转运蛋白在视网膜铁超载期间下调。 铁改变神经元细胞对 β-OHB 的摄取，导致细胞死亡的表观遗传机制。 过去 10 年的铁稳态培训支持了三个拟议目标，这是一项充满活力的研究 SLU 的环境，以及与高级教师的持续专业指导和合作。 该项目的完成将增进我们对铁如何改变酮代谢并驱动酮代谢的理解 进入新的和尚未开发的领域，例如有效利用酮体的代谢重编程。