CHRONO-MECHANISMS of CARDIOMETABOLIC PHARMACOLOGY

项目总结 糖皮质激素是一种保守的多效性激素，调节能量利用的昼夜周期。 并储存在我们几乎所有的器官中。心脏中的营养代谢是适应高能量的关键 对昼夜节律振荡和/或糖尿病心肌病等疾病状态的需求。糖皮质激素强效 它们通过糖皮质激素受体(GR)发挥作用，而GR是正常心脏功能所必需的。的确， 人工合成的糖皮质激素常用于抢救代谢性酸中毒和抑郁的心脏疾病 功能障碍，如低心排血量综合征。然而，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。因此，分子和昼夜节律 人工合成的糖皮质激素及其受体对心脏代谢的影响仍未解决。vbl.使用 以营养不良小鼠为慢性横纹肌损伤模型，发现间歇给药(每周一次) 糖皮质激素可提高营养不良肌肉和心脏的营养利用和胰岛素敏感性。在这里，我 假设间歇性糖皮质激素改善了营养不良心脏以外的心脏代谢健康，并可以 被用来对抗糖尿病心肌病。在小鼠中，内源性皮质酮和皮质酮的振荡 生物钟因素为急性GR对药物激活的反应创造了一个关键的时间窗口 在白天的早期阶段。事实上，我发现间歇性强的松的白天疗法--但不是夜间疗法 改善野生型心脏的心功能和代谢。昼夜给药是关键的 强的松驱动的GR程序提高线粒体能力并激活代谢调节因子KLF15 和AMPK。此外，昼夜泼尼松降低了3-羟基异丁酸(3-HIB)，这是分解代谢受损的生物标志物 支链氨基酸(BCAA)与糖尿病胰岛素抵抗的关系。因此，我假设计时器- 糖皮质激素通过GR、KLF15和AMPK促进心脏代谢健康 活化，降低3-HIB作为糖尿病心肌病代谢挽救的生物标志物。为了测试这一点 假设，我们将阐明该项目以测试三个互补的机制：在目标1中，我们将测试 昼夜泼尼松对线粒体能力影响中对GR和时钟因子BMAL的需求 在目标2中，我们将定义GR激活的KLF15的需求和表观基因组机制 在目标3中，我们将重塑心肌细胞中营养物质的利用以响应泼尼松的计时剂量 确定AMPK和BCAA氧化在调节昼夜间歇强的松作用中的作用 糖尿病心肌病的代谢灵活性和3-HIB水平。这项提议描绘了一条新的道路， 利用心脏对合成糖皮质激素的昼夜门控反应进行心脏新陈代谢抢救。 定义了糖皮质激素级联反应和生物钟之间前所未有的相互作用机制， 该项目将提供证据，证明有时间限制的间歇给药是糖皮质激素作用的“触发开关” 心脏代谢，使这些药物在心脏代谢健康中从“促糖尿病”转变为“抗糖尿病”。

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.