Molecular Basis of Exercise-induced Changes in HDL Function

高密度脂蛋白(高密度脂蛋白)颗粒具有多种动脉粥样硬化保护特性，包括去除多余的 外周组织中的胆固醇，抑制血管炎症，减少氧化应激。它是 认为高密度脂蛋白的功能是由与高密度脂蛋白颗粒结合的分子介导的，这些分子包括蛋白质，脂类， 和microRNAs。高密度脂蛋白的功能和组成已被证明在各种疾病状态下受损， 高密度脂蛋白功能的测量是心血管疾病风险的强大、独立的预测因素。最近的工作有 表明运动训练以剂量特异性的方式改善高密度脂蛋白的功能。因此，该委员会的总体目标是 建议的研究是检查运动剂量和类型对高密度脂蛋白功能的影响，并确定临床 以及运动引起的高密度脂蛋白功能变化的分子因素。拟议的研究将利用 现有的数据和样本来自NIH资助的四个大型、已完成的临床锻炼试验(N=1224)，以测试 研究假设：传统家族研究(N=731；5个月，健康成年人的有氧剂量相同)，STRRIDE AT/RT(N=144；8个月，对患有轻度血脂异常的超重成年人进行有氧训练、阻力训练或联合训练)， STRRIDE-PD(N=175；6个月，4组有氧运动量和/或强度不同的成年人 糖尿病)和HART-D研究(N=174；9个月，时间匹配的有氧、耐力或组合训练 糖尿病患者)。具体地说，目标1将考察运动量、运动强度和运动类型如何影响 高密度脂蛋白功能的三个指标(胆固醇流出能力、抗炎和抗氧化特性)和 运动对高密度脂蛋白功能的影响是否因种族、性别和/或代谢特征而不同(例如，糖尿病， 代谢综合征、肥胖)。目标2将检查运动训练对高密度脂蛋白蛋白质组的影响 Lipoidome和HDLmicroRNA图谱，并验证性别和种族特定的HDL分子签名 预测运动引起的高密度脂蛋白功能的变化。此外，AIM 2将集成生成的HDL语言 功能和高密度脂蛋白组成数据，以及可用的基因组、代谢和肌肉基因表达数据 识别与运动引起的高密度脂蛋白功能改变相关的新基因、途径和网络。这个 拟议的研究将确定改善高密度脂蛋白功能和 将确定这些功能变化背后的特定分子群。识别临床和分子 运动诱导的高密度脂蛋白功能变化的预测指标可以帮助提供有针对性的运动计划 特定的性种族疾病群体，以最大限度地提高收益。

High-density lipoprotein (HDL) particles have multiple atheroprotective properties, including removal of excess cholesterol from peripheral tissues, inhibition of vascular inflammation, and reduction of oxidative stress. It is thought that HDL function is mediated by the molecules bound to HDL particles, which include proteins, lipids, and microRNAs. HDL function and composition have been shown to be impaired in various disease states and measures of HDL function are strong, independent predictors of cardiovascular disease risk. Recent work has shown that exercise training improves HDL function in a dose-specific manner. Thus, the overall goal of the proposed study is to examine the effects of exercise dose and type on HDL function and identify the clinical and molecular factors underlying exercise-induced changes in HDL function. The proposed study will utilize existing data and samples from four large, completed NIH-funded clinical exercise trials (N=1224) to test the study hypotheses: HERITAGE Family Study (N=731; 5 mos, same aerobic dose in healthy adults), STRRIDE AT/RT (N=144; 8 mos, aerobic, resistance, or combination training in overweight adults with mild dyslipidemia), STRRIDE-PD (N=175; 6 mos, 4 groups differing in aerobic exercise amount and/or intensity in adults with pre- diabetes), and HART-D study (N=174; 9 mos, time-matched aerobic, resistance, or combination training in diabetics). Specifically, Aim 1 will examine how exercise amount, exercise intensity, and exercise type affect three measures of HDL function (cholesterol efflux capacity, anti-inflammatory and anti-oxidant properties) and whether the exercise effects on HDL function differ by race, sex, and/or metabolic profile (e.g., diabetes, metabolic syndrome, obesity). Aim 2 will examine the effects of exercise training on the HDL proteome, HDL lipidome, and HDL microRNA profiles and validate sex- and race-specific HDL molecular signatures that predict exercise-induced changes in HDL function. Furthermore, Aim 2 will integrate the generated HDL function and HDL composition data with available genomic, metabolomic, and muscle gene expression data to identify novel genes, pathways, and networks associated with exercise-induced changes in HDL function. The proposed research will determine the amount, intensity, and type of exercise that improves HDL function and will identify specific groups of molecules underlying these functional changes. Identifying clinical and molecular predictors of exercise-induced changes in HDL function could help provide targeted exercise programs tailored to specific sex-race-disease groups to maximize the benefits.