Atrial Natriuretic Peptide and Regulation of Cardiometabolic Health: A Genotype-Guided Human Physiological Study

心钠素和心脏代谢健康的调节：基因型引导的人类生理学研究

• 批准号: 10627996
• 负责人: Pankaj Arora
• 金额: $ 74.11万
• 依托单位: UNIVERSITY OF ALABAMA AT BIRMINGHAM
• 依托单位国家: 美国
• 财政年份: 2022
• 资助国家: 美国
• 起止时间: 2022-06-01 至 2027-04-30
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10627996
• 关键词: 3' Untranslated Regions; Adipocytes; Adult; Age; Alleles; Atrial Natriuretic Factor; Binding; Biological; Black Populations; Blood; Blood Pressure; Blood Vessels; Body mass index; Brown Fat; Cardiac; Cardiac Myocytes; Cardiometabolic Disease; Data; Development; Diabetes Mellitus; Diet; Energy Metabolism; Enrollment; Ensure; Exercise; Exercise Test; Fatty acid glycerol esters; Female; Frequencies; Gene Expression; Genes; Genetic Carriers; Genetic Variation; Genotype; Glucose; Glycerol; Health; Homeostasis; Hormones; Hour; Human; Hyperinsulinism; In Vitro; Indirect Calorimetry; Individual; Insulin; Insulin Resistance; Lipolysis; Low Prevalence; Mediating; Messenger RNA; Metabolic; Metabolic syndrome; MicroRNAs; Minor; Natriuresis; Natriuretic Peptides; Nonesterified Fatty Acids; Obesity; Oral; Participant; Pathway interactions; Phenotype; Physiological; Plasma; Population; Production; Protocols documentation; RNA; Regulation; Rest; Risk; Role; Sampling; Skeletal Muscle; Specificity; Standardization; System; Testing; Therapeutic; Thinness; United States; Whole Blood; Work; blood glucose regulation; burden of illness; cardiometabolism; exercise intervention; genetic variant; improved; in vivo; innovation; insight; insulin sensitivity; lipid biosynthesis; novel; novel therapeutics; prevent; primary outcome; response; salt intake; therapeutic RNA; therapeutic target

PROJECT SUMMARY The cardiometabolic disease burden is increasing in the United States. The atrial natriuretic peptide (ANP) hormone contributes to the regulation of glucose utilization, energy homeostasis and is a major determinant of cardiometabolic health. We have demonstrated that a common genetic variant in the ANP gene (rs5068) is associated with higher ANP levels and a more favorable cardiometabolic profile. We have also identified that microRNA-425 (miR-425) decreases the production of ANP. The favorable genetic variant (rs5068) prevents the binding of miR-425 and ensures adequate ANP production. Thus, miR-425 acts only among those with low ANP genotype, i.e., those without the rs5068 genetic variant. We have also demonstrated that an oral glucose challenge reduces ANP levels, whereas an exercise challenge increases ANP levels. However, the impact of the ANP genotype on the ANP response to glucose challenge and exercise challenge has not been previously examined. We have demonstrated that miR-425 is glucose-responsive and may regulate the ANP response to metabolic perturbations. The response of miR-425 to glucose challenge, exercise challenge, and its relationship with energy expenditure (EE) is not known in humans. We hypothesize that individuals with low ANP genotype will (1) have a greater suppression of ANP by glucose challenge, (2) have lower resting and exercise EE, and (3) demonstrate the responsiveness of miR-425 to metabolic perturbations (glucose challenge and exercise challenge). We propose to conduct a genotype-guided study by performing detailed metabolic profiling among individuals with high and low ANP genotypes. In our Aim 1, we will enroll 200 healthy adults (50 with high ANP genotype and 150 with low ANP genotype), and we will assess the difference in response of MRproANP to a glucose challenge by genotype groups. We will also assess the change in the glucose and insulin levels subsequent to glucose challenge between high and low ANP genotype groups. In Aim 2, we will assess the difference in EE (during rest and during exercise) between the two genotype groups. We will also assess the difference between the two genotype groups in terms of the response of ANP, glucose, insulin, and markers of fat breakdown to the standardized exercise challenge. In Aim 3, we will assess if there is a change in miR-425 expression after glucose and exercise challenge among those with low ANP genotype. We will also assess the association of change in miR-425 expression with the change in MRproANP, glucose, and insulin levels following respective metabolic perturbations (glucose challenge and exercise challenge). The detailed metabolic profiling of participants based on their ANP genotype will provide insights into the role of the ANP system in the regulation of cardiometabolic health and generate evidence supporting the biological basis for developing RNA-based novel treatment approaches to prevent and treat cardiometabolic diseases.

项目摘要 在美国，心脏代谢疾病负担正在增加。心房尿液肽（ANP） 激素有助于调节葡萄糖利用，能量稳态，是主要的决定因素 心脏代谢健康。我们已经证明了ANP基因中的常见遗传变异（RS5068） 与较高的ANP水平和更有利的心脏代谢概况有关。我们还确定了 MicroRNA-425（miR-425）降低了ANP的产生。有利的遗传变异（RS5068） 防止miR-425的结合，并确保足够的ANP产生。因此，miR-425仅在 患有ANP基因型低的人，即没有RS5068遗传变异的人。我们也证明了 口服葡萄糖挑战降低了ANP的水平，而运动挑战则增加了ANP水平。 但是，ANP基因型对ANP响应对葡萄糖挑战和运动的影响 挑战以前尚未检查。我们已经证明miR-425是葡萄糖响应性的 并可能调节ANP对代谢扰动的反应。 mir-425对葡萄糖的反应 挑战，运动挑战及其与能源消耗（EE）的关系在人类中尚不清楚。 我们假设ANP基因型较低的个体将（1）通过 葡萄糖挑战，（2）具有较低的休息和运动EE，（3）证明了 miR-425用于代谢扰动（葡萄糖挑战和运动挑战）。我们建议进行 基因型引导的研究通过在ANP高和低的个体中进行详细的代谢分析。 基因型。在我们的目标1中，我们将招募200名健康成年人（50名具有高ANP基因型的成年人，150个患有低的成年人 ANP基因型），我们将通过通过 基因型组。我们还将评估葡萄糖之后的葡萄糖和胰岛素水平的变化 高和低ANP基因型组之间的挑战。在AIM 2中，我们将评估EE的差异 （在休息期间和运动过程中）在两个基因型组之间。我们还将评估差异 在两个基因型组之间就ANP，葡萄糖，胰岛素和脂肪标记的反应而言 分解标准化运动挑战。在AIM 3中，我们将评估mir-425是否发生变化 葡萄糖后的表达和运动挑战率低的人群低。我们还将评估 miR-425表达变化与MRProANP，葡萄糖和胰岛素水平的变化的关联 遵循各自的代谢扰动（葡萄糖挑战和运动挑战）。详细 基于ANP基因型的参与者的代谢分析将提供有关ANP角色的见解 系统调节心脏代谢健康，并生成支持生物学基础的证据 开发基于RNA的新型治疗方法，以预防和治疗心脏代谢疾病。