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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（BP）昼夜节律对人体健康至关重要，如早晨血压