CHRONO-MECHANISMS of CARDIOMETABOLIC PHARMACOLOGY

心脏代谢药理学的时间机制

• 批准号: 10271560
• 负责人: Mattia Quattrocelli
• 金额: $ 39.75万
• 依托单位: CINCINNATI CHILDRENS HOSP MED CTR
• 依托单位国家: 美国
• 财政年份: 2021
• 资助国家: 美国
• 起止时间: 2021-09-21 至 2023-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10271560
• 关键词: ARNTL gene; Ablation; Acute; Alleles; Antidiabetic Drugs; Binding; Biological Markers; Branched-Chain Amino Acids; Cardiac; Cardiac Myocytes; Cardiovascular Diseases; Catabolism; Chronic; Clinical Trials; Corticosterone; Data; Depressed mood; Diabetes Mellitus; Diabetic mouse; Disease; Dose; Glucocorticoid Receptor; Glucocorticoids; Glucose; Half-Life; Health; Heart; Hormones; Impairment; Injury; Insulin Resistance; Intake; Knock-in; Link; Low Cardiac Output Syndrome; Mediating; Metabolic; Metabolic acidosis; Metabolic syndrome; Metabolism; Mitochondria; Modeling; Molecular; Mus; Muscle; Nuclear Translocation; Nutrient; Obesity; Organ; Patients; Pharmacology; Phase; Prednisone; Prodrugs; Publishing; Receptor Activation; Regimen; Role; Steroids; Striated Muscles; Testing; Time; Transgenic Mice; Transgenic Model; base; cardiometabolism; circadian; circadian pacemaker; circadian regulation; combat; diabetic; diabetic cardiomyopathy; epigenomics; flexibility; heart circulation; heart function; heart metabolism; improved; insulin sensitivity; novel; nutrient metabolism; oxidation; programs; receptor; receptor sensitivity; response; transcription factor; uptake; virtual

PROJECT SUMMARY Glucocorticoid steroids are conserved pleiotropic hormones regulating the circadian cycle of energy utilization and storage in virtually all our organs. Nutrient metabolism in the heart is critical to adapt the high energy demand to circadian oscillations and/or diseased states like diabetic cardiomyopathy. Glucocorticoids exert their effects through the glucocorticoid receptor (GR), which is required for normal heart function. Indeed, synthetic glucocorticoids are routinely used to rescue cardiac conditions of metabolic acidosis and depressed function, such as low cardiac output syndrome. However, chronic GR over-stimulation with synthetic glucocorticoids promotes metabolic syndrome and cardiovascular diseases. Thus, the molecular and circadian effects of synthetic glucocorticoids and their receptor on cardiac metabolism are still unresolved. Using dystrophic mice as model of chronic striated muscle injury, I discovered that intermittent dosing (once-weekly) of glucocorticoids boosts nutrient utilization and insulin sensitivity in dystrophic muscle and heart. Here I postulate that intermittent glucocorticoids improve cardiometabolic health beyond the dystrophic heart and can be exploited to combat diabetic cardiomyopathy. In mice, oscillations of endogenous corticosterone and circadian clock factors create a critical time window for acute GR responsiveness to pharmacological activation in the early diurnal phase. Indeed, I found that diurnal – but not nocturnal – regimens of intermittent prednisone improved cardiac function and metabolism in wildtype hearts. Diurnal administration was critical for the prednisone-driven GR program to boost mitochondrial capacity and activate the metabolic regulators KLF15 and AMPK. Also, diurnal prednisone reduced 3-hydroxyisobutyrate (3-HIB), biomarker of impaired catabolism of branched chain amino acids (BCAA) and insulin resistance in diabetes. Thus, I hypothesize that chrono- pharmacology with diurnal glucocorticoids promotes cardiometabolic health through GR, KLF15 and AMPK activation, and reduces 3-HIB as biomarker of metabolic rescue in diabetic cardiomyopathy. To test this hypothesis, we will articulate the project to test three complementary mechanisms: in Aim 1, we will test the requirement for GR and the clock factor BMAL in the effects of diurnal prednisone on mitochondrial capacity in heart; in Aim 2, we will define requirement and epigenomic mechanisms for the GR-activated KLF15 in reshaping nutrient utilization in cardiomyocytes in response to prednisone chrono-dosing; in Aim 3, we will determine the role of AMPK and BCAA oxidation in mediating the effects of diurnal intermittent prednisone on metabolic flexibility and 3-HIB levels in diabetic cardiomyopathy. This proposal charts a novel path to cardiometabolic rescue by exploiting the circadian-gated response to synthetic glucocorticoids in heart. Defining unprecedented mechanisms of interplay between glucocorticoid cascades and circadian clock, the project will provide evidence for time-restricted intermittent dosing as “flip switch” of glucocorticoid action in heart metabolism, converting these drugs from “pro-diabetic” to “anti-diabetic” in cardiometabolic health.

项目摘要 糖皮质激素是保守的多效激素，用于调查能量利用的昼夜节律周期 并在我们的所有器官中存储。心脏中的营养代谢对于适应高能量至关重要 对昼夜节律振荡和/或糖尿病心肌病（例如糖尿病心肌病）的需求。糖皮质激素运动 它们通过糖皮质激素受体（GR）的作用，这是正常心脏功能所必需的。的确， 合成糖皮质激素通常用于营救代谢性酸中毒的心脏条件和抑郁症 功能，例如低心输出综合征。但是，慢性GR过度刺激与合成 糖皮质激素促进代谢综合征和心血管疾病。那，分子和昼夜节律 合成糖皮质激素及其受体对心脏代谢的影响仍未解决。使用 营养不良小鼠是慢性肌肉损伤的模型，我发现间歇性给药（每周一次） 糖皮质激素可提高营养不良肌肉和心脏中的胰岛素敏感性。我在这里 假设间歇性糖皮质激素可改善心脏多障碍心脏的心脏代谢健康，并且可以 探索以战斗糖尿病心肌病。在小鼠中，内源性皮质酮和 昼夜节律因素创造了一个关键的时间窗口，以使急性GR反应能力对药物激活 的确，我发现昼夜的昼夜性是间歇性泼尼松的方案 野生型心脏中改善心脏功能和代谢。昼夜管理对于 泼尼松驱动的GR计划，以提高线粒体能力并激活代谢调节剂KLF15 和AMPK。此外，昼夜泼尼松降低了3-羟基异丁酸（3-HIB），分解代谢受损的生物标志物 糖尿病中的分支链氨基酸（BCAA）和胰岛素抵抗。那我假设计时 昼夜糖皮质激素的药理学通过GR，KLF15和AMPK促进心脏代谢健康 激活，并减少3-HIB作为糖尿病心肌病代谢营救的生物标志物。测试这个 假设，我们将阐明该项目以测试三个完整的机制：在AIM 1中，我们将测试 GR和时钟因子BMAL对昼夜泼尼松对线粒体能力的影响的要求 心;在AIM 2中，我们将定义GR活化的KLF15的要求和表观基因组机制 响应泼尼松的剂量剂量，在心肌细胞中重塑营养利用；在AIM 3中，我们将 确定AMPK和BCAA氧化在介导昼夜间歇性泼尼松对的影响中的作用 糖尿病心肌病的代谢柔韧性和3-HIB水平。该提议为通往 通过利用心脏中对合成糖皮质激素的昼夜节律反应来挽救心脏代谢。 定义糖皮质激素级联和昼夜节律之间相互作用的前所未有的机制， 项目将提供段落间歇剂量作为糖皮质激素作用的“翻转开关”的证据 心脏代谢，将这些药物从心脏代谢健康中的“促糖尿病”转化为“抗糖尿病”。