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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：
10308681
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 2023-10-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10308681
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 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类健康至关重要，就像早晨的血压一样浪涌与威胁生命的心血管事件的发生率增加有关。此外，颠覆血压昼夜节律，它发生在高达75%的糖尿病患者中，正在成为未来的一个指标靶器官损伤和心血管预后不良。然而，血压昼夜节律的机制糖尿病患者的节律被打乱在很大程度上是未知的，而恢复被打乱的BP的有效策略糖尿病的昼夜节律尚未确定。我们的初步研究发现，通过限制食物可利用至活动期的时间(Atrf)对糖尿病db/db小鼠提供了显著的保护。来自血压昼夜节律的严重扰乱。此外，BMAL1，一个必需的时钟基因，也是必需的胰升糖素样肽-1(GLP-1)受体激活模拟血压昼夜节律的保护 ATRF。这些有趣的发现表明，ATRF可以作为一种新的策略来促进正常的BP 昼夜节律，从而显著改善糖尿病患者的心血管预后。这个目前的提案将通过测试活动时间-活动时间-的具体假设来检验这种新的令人兴奋的可能性限制进食(ATRF)或GLP-1激活可恢复正常的平滑肌和肾脏BMAL1和交感神经振荡因此保护糖尿病小鼠免受血压昼夜节律的干扰。三个具体目标是1)。确定BMAL1在糖尿病和糖尿病中调节失调的机制由ATRF修复。2)。验证ATRF通过血管紧张素转换酶保护血压昼夜节律糖尿病患者肾脏BMAL1的变化。3)。将ATRF定义为一种新的慢性营养疗法，并将GLP-1作为保护糖尿病患者血压昼夜节律的新药物疗法。我们将监测昼夜节律血压节律、食物摄入量、BMAL1调节、血管平滑肌功能和信号、肾脏功能，以及在自由和ATRF喂养方案下的交感神经调节。各种鼠标将使用的模型有糖尿病db/db小鼠、db/db-per2Luc小鼠、高脂饮食喂养的小鼠、平滑肌和肾脏BMAL1基因敲除小鼠。