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.

正常血压 (BP) 昼夜节律对人类健康至关重要，因为早晨血压激增与危及生命的心血管事件的发生率增加有关。此外，扰乱高达 75% 的糖尿病患者存在血压昼夜节律，这种情况正在成为未来的一个指标靶器官损伤和不良心血管结局。然而，血压昼夜节律的机制糖尿病引起的节律紊乱在很大程度上尚不清楚，恢复紊乱的血压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，通过限制食物可摄取时间到活动期 (ATRF) 对糖尿病 db/db 小鼠提供了显着的保护血压昼夜节律严重紊乱。此外，还需要必需的时钟基因 BMAL1 胰高血糖素样肽-1 (GLP-1) 受体激活可通过以下方式模拟对血压昼夜节律的保护 ATRF。这些有趣的发现表明 ATRF 可以作为促进正常血压的新策略昼夜节律，从而显着改善糖尿病患者的心血管预后。这当前的提案将通过测试活跃时间这一具体假设来检验这一令人兴奋的新可能性限制进食 (ATRF) 或 GLP-1 激活可恢复正常平滑肌和肾 BMAL1 和因此，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。这三个具体目标是 1)。确定 BMAL1 在糖尿病中失调的机制由 ATRF 恢复。 2）。检验 ATRF 通过平滑肌和保护血压昼夜节律的假设糖尿病中的肾 BMAL1。 3）。将 ATRF 定义为一种新型的时间营养疗法，并以 GLP-1 为目标保护糖尿病患者血压昼夜节律的新药物疗法。我们会监测昼夜节律血压节律、食物摄入、BMAL1 调节、血管平滑肌功能和信号传导、肾脏随意进食和 ATRF 喂养方案下的功能和交感神经调节。各种鼠标将使用的模型有糖尿病 db/db 小鼠、db/db-per2Luc 小鼠、高脂饮食喂养小鼠、平滑肌和肾BMAL1基因敲除小鼠。