Harnessing novel glucocorticoid biology to treat diabetic cardiomyopathy

利用新型糖皮质激素生物学治疗糖尿病心肌病

• 批准号: 10733533
• 负责人: Mattia Quattrocelli
• 金额: $ 40.13万
• 依托单位: CINCINNATI CHILDRENS HOSP MED CTR
• 依托单位国家: 美国
• 财政年份: 2023
• 资助国家: 美国
• 起止时间: 2023-08-01 至 2027-06-30
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10733533
• 关键词: ARFIP2 gene; ARNTL gene; Ablation; Adverse effects; Antioxidants; Biogenesis; Biology; Cardiac; Cardiac Myocytes; Cardiomyopathies; Cardiovascular Diseases; Ceramidase; Ceramides; Cessation of life; Chronic; Circadian Dysregulation; Circadian Rhythms; Clinical Trials; Corticosterone; Cues; Darkness; Diabetic mouse; Dimensions; Dose; Exercise; Exercise Tolerance; Failure; Frequencies; Functional disorder; Genes; Genetic Transcription; Glucocorticoid Receptor; Glucocorticoids; Glucose; Heart; Human; Impairment; Insulin Resistance; Intake; Ischemia; Light; Link; Measures; Mediating; Metabolic; Metabolism; Mitochondria; Modeling; Mus; Myocardial Infarction; Non-Insulin-Dependent Diabetes Mellitus; Obesity; Outcome; Oxidative Stress; Pathology; Patients; Periodicity; Pharmaceutical Preparations; Pharmacology; Phase; Prednisone; Pyruvate; Role; Signal Transduction; Specific qualifier value; Stimulus; Testing; Therapeutic Intervention; Thinness; Time; adiponectin; circadian; circadian pacemaker; cofactor; diabetic; diabetic cardiomyopathy; flexibility; functional improvement; glucose metabolism; heart function; heart metabolism; improved; insulin sensitivity; lifestyle intervention; novel; oxidation; programs; pyruvate carrier; response; safety outcomes; transcription factor

PROJECT SUMMARY Diabetic cardiomyopathy is the leading cause of complications in type-2 diabetes. The diabetic heart features metabolic insults that promote its metabolic inflexibility and failure, particularly insulin resistance, impaired glu- cose oxidation and loss of NAD+ biogenesis. The cardiomyocyte-specific glucocorticoid receptor (GR) is im- portant for heart function, but the GR-dependent metabolic mechanisms of glucocorticoids (GCs) in cardiomyo- cytes remain unknown. GR activity is regulated by the circadian clock but the extent to which the GR regulates the cardiomyocyte clock is still unknown. The GR activates its co-factor KLF15, which regulates cardiac metab- olism and promotes oscillating transcriptional programs in heart. However, a direct role for KLF15 in regulating circadian clock genes is still unknown. The circadian clock factor BMAL1 promotes oscillating NAD+ repletion and supports cardiac clock and function in a cardiomyocyte-autonomous fashion. However, the clock response to GC signaling in heart remains unknown. Recently, we have shown two interconnected time dimensions that harness benefits from detriments of GC pharmacology: circadian time-of-intake and chronic frequency-of- intake. Circadian-specific prednisone intermittence has shown positive outcomes of safety and benefits in a pilot clinical trial, underscoring relevance and feasibility in humans. Our preliminary findings with obese diabetic mice suggest that light-phase intermittent prednisone rescues NAD+ biogenesis, glucose metabolism and ceramide lipotoxicity in heart, blunting diastolic dysfunction. This raises the unanticipated idea of repurposing GC drugs to treat diabetic cardiomyopathy, but the mechanism underpinning this action must still be identified. Based on our findings in three cardiomyocyte-restricted inducible KO models, we discovered a new GR-KLF15-BMAL1 mechanism regulating clock and metabolism in cardiomyocytes. We test here the overarching hypothe- sis that this cardiomyocyte-autonomous axis is triggered by specific GC timing and rescues cardiomy- opathy in type-2 diabetes. In Aim 1, we will identify the circadian cue gating the circadian-specific effect of exogenous glucocorticoids in heart. We will test the hypothesis that the rhythmic trough of endogenous GCs is the circadian cue mediating the circadian-specific effects of exogenous GCs in heart. In Aim 2, we will determine the extent to which the cardiomyocyte clock discriminates beneficial versus deleterious outcomes of chronic GC frequency. We will test the hypothesis that cardiomyocyte-specific BMAL1 is the discriminating factor in the dia- betic heart response to chronic GC effects. In Aim 3, we will identify the mechanisms promoting insulin sensitivity and glucose oxidation by the cardiomyocyte-specific GR-KLF15 axis. We will test the hypothesis that the cardi- omyocyte GR-KLF15 axis rescues metabolic flexibility in the diabetic heart through a concerted program of ceramide reduction and pyruvate oxidation, dependent on timing-specific GC exposure. In summary, our study resolves the role of cardiomyocyte GR biology in heart metabolism, while identifying translational cues and drug- gable mechanisms of GR-clock interplay for diabetic cardiomyopathy.

项目摘要 糖尿病性心肌病是2型糖尿病并发症的主要原因。糖尿病心脏的特点 代谢损伤，促进其代谢能力和失败，特别是胰岛素抵抗，损害血糖， 碳氧化和NAD+生物合成的损失。心肌细胞特异性糖皮质激素受体（GR）是心肌细胞特异性糖皮质激素受体。 重要的心脏功能，但糖皮质激素（GC）在心肌细胞GR依赖的代谢机制， 细胞仍然未知。GR活性受生物钟调节，但GR调节的程度 心肌细胞的生物钟仍然是未知的。GR激活其辅助因子KLF 15，其调节心脏代谢。 olism和促进心脏中的振荡转录程序。然而，KLF 15在调节 生物钟基因仍然是未知的。生物钟因子BMAL 1促进振荡NAD+补充 并以心肌细胞自主的方式支持心脏时钟和功能。时钟响应 心脏中GC信号传导的作用仍然未知。最近，我们展示了两个相互关联的时间维度， 利用GC药理学的优势：昼夜摄入时间和慢性频率 摄入昼夜节律特异性泼尼松耐受性在试点中显示出安全性和益处的积极结果 临床试验，强调人类的相关性和可行性。我们对肥胖糖尿病小鼠的初步发现 提示轻时相间歇性泼尼松可挽救NAD+生物合成、葡萄糖代谢和神经酰胺 心脏脂毒性，减缓舒张功能障碍这提出了一个意想不到的想法，重新利用GC药物， 治疗糖尿病性心肌病，但这种作用的机制仍有待确定。基于我们 在三种心肌细胞限制性诱导型KO模型中，我们发现了一种新的GR-KLF 15-BMAL 1 调节心肌细胞生物钟和代谢的机制。我们在这里测试的首要hypothe- 这个心肌细胞自主轴是由特定的GC时间触发的，并挽救了心脏， 2型糖尿病的发病机制在目标1中，我们将确定昼夜节律线索门控的昼夜节律特异性效应， 心脏外源性糖皮质激素。我们将检验内源性GC的节律性低谷是 昼夜节律线索介导外源性GCs在心脏中的昼夜节律特异性效应。在目标2中，我们将确定 心肌细胞生物钟区分慢性GC有益与有害结果的程度 频率.我们将检验心肌细胞特异性BMAL 1是分化因子的假设。 心脏对慢性GC效应的反应。在目标3中，我们将确定促进胰岛素敏感性的机制 和通过心肌细胞特异性GR-KLF 15轴的葡萄糖氧化。我们将检验心脏- 肌细胞GR-KLF 15轴通过以下协调程序挽救糖尿病心脏的代谢灵活性： 神经酰胺还原和丙酮酸氧化，依赖于时间特异性GC暴露。总之，我们的研究 解决了心肌细胞GR生物学在心脏代谢中的作用，同时确定了翻译线索和药物- 糖尿病心肌病GR-时钟相互作用的机制