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Targeting timing of food intake as a novel strategy against disruption of blood pressure circadian rhythm in diabetes

以食物摄入时间为目标作为对抗糖尿病患者血压昼夜节律紊乱的新策略

基本信息

批准号：
10063547
负责人：
MING C GONG
金额：
$ 60.11万
依托单位：
UNIVERSITY OF KENTUCKY
依托单位国家：
美国
项目类别：
财政年份：
2019
资助国家：
美国
起止时间：
2019-01-15 至 2022-10-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10063547
关键词：
ARNTL gene Affect Agonist Blood Pressure Calories Cardiovascular Diseases Cardiovascular system Circadian Rhythms Data Diabetes Mellitus Diabetic Angiopathies Diabetic mouse Eating Event Excretory function Food Functional disorder Future GLP-I receptor Genes Glucagon Goals Health High Fat Diet Human Incidence Intake Kidney Knockout Mice Life Light Link Liver Macronutrients Nutrition Metabolism Monitor Mus Muscle function Norepinephrine Nuclear Obesity Organ Outcome Peptides Pharmacology Prevalence Prognosis Receptor Activation Regimen Regulation Renal function Reporting Rho-associated kinase Role Severities Signal Transduction Smooth Muscle Smooth Muscle Myocytes Sympathetic Nervous System Testing Time Time-restricted feeding Type 2 diabetic Variant Vascular Smooth Muscle circadian db/db mouse diabetic diabetic patient fasudil feeding gender difference glucagon-like peptide 1 improved indexing inhibitor/antagonist mouse model neurotensin mimic 1 novel novel strategies novel therapeutic intervention organ injury pre-clinical prevent protective effect urinary

项目摘要

The normal blood pressure (BP) circadian rhythm is essential to human health, as morning BP surge is associated with increased incidence of life-threatening cardiovascular events. Moreover, disruption of BP circadian rhythm, which occurs in up to 75% of diabetic patients, is emerging as an index for future target organ injury and poor cardiovascular outcomes. However, the mechanism by which BP circadian rhythm is disrupted in diabetes is largely unknown, and an effective strategy to restore the disrupted BP circadian rhythm in diabetes has not yet been identified. Our preliminary studies found that by limiting the time of food available to the active period (ATRF) provided striking protection of the diabetic db/db mice from the severe disruption of BP circadian rhythm. Moreover, BMAL1, an obligatory clock gene, is required for and glucagon-like peptide-1 (GLP-1) receptor activation mimics the protection of BP circadian rhythm by ATRF. These intriguing findings suggest that ATRF can serve as a novel strategy to promote normal BP circadian rhythms, thus significantly improving the cardiovascular prognosis of diabetic patients. The current proposal will examine this new exciting possibility by testing the specific hypothesis that active time- restricted feeding (ATRF) or GLP-1 activation restores normal smooth muscle and renal BMAL1 and sympathetic oscillations thus protects diabetic mice from disruptions of blood pressure circadian rhythm. The three specific aims are 1). Determine the mechanism by which BMAL1 is dysregulated in diabetes and restored by ATRF. 2). Test the hypothesis that ATRF protects BP circadian rhythm via smooth muscle and renal BMAL1 in diabetes. 3). Define ATRF as a novel chrononutritional therapy and targeting GLP-1 as a new pharmacological therapy to protect BP circadian rhythm in diabetes. We will monitor the circadian rhythms of BP, food intake, BMAL1 regulation, vascular smooth muscle function and signaling, renal function, and sympathetic regulation under ad libitum and ATRF feeding regimens. The various mouse models will be used are diabetic db/db mice, db/db-per2Luc mice, high-fat diet fed mice, smooth muscle and renal BMAL1 knockout mice.

正常的血压昼夜节律对人体健康至关重要，如早晨血压浪涌与危及生命的心血管事件的发生率增加有关。此外，中断血压昼夜节律，发生在高达75%的糖尿病患者，正在成为未来的指标靶器官损伤和不良心血管结局。然而，BP昼夜节律的机制糖尿病患者的血压节律紊乱在很大程度上是未知的，糖尿病的昼夜节律尚未确定。我们的初步研究发现，通过限制活动期食物可利用时间（ATRF）对糖尿病db/db小鼠具有显著的保护作用血压昼夜节律的严重紊乱此外，BMAL 1，一个强制性的时钟基因，是必需的胰高血糖素样肽-1（GLP-1）受体激活通过以下方式模拟BP昼夜节律的保护作用： ATRF。这些有趣的发现表明，ATRF可以作为一种新的策略，以促进正常的血压昼夜节律，从而显著改善糖尿病患者的心血管预后。的目前的建议将通过测试特定的假设，即活跃时间- 限制进食（ATRF）或GLP-1激活可恢复正常平滑肌和肾脏BMAL 1，因此，交感神经振荡可以保护糖尿病小鼠免受血压昼夜节律的破坏。三个具体目标是1）。确定BMAL 1在糖尿病中失调的机制，由ATRF恢复。2）。检验ATRF通过平滑肌保护血压昼夜节律的假设，糖尿病患者的肾脏BMAL 1。3）。将ATRF定义为一种新型的时间营养疗法，将GLP-1作为靶点，保护糖尿病患者血压昼夜节律的新药物治疗。我们会监控他们的昼夜节律血压节律，食物摄入，BMAL 1调节，血管平滑肌功能和信号传导，肾功能，以及在随意和ATRF喂养方案下的交感神经调节。各种鼠标将使用的模型是糖尿病db/db小鼠、db/db-per 2Luc小鼠、高脂肪饮食喂养的小鼠、平滑肌和肾BMAL 1敲除小鼠。