Effects of Aerobic Exerise on EPCs and Vascular Dysfunction in Aging and T2DM

有氧运动对衰老和 T2DM 中 EPC 和血管功能障碍的影响

• 批准号: 8530142
• 负责人: Steven J Prior
• 金额: $ 17.73万
• 依托单位: UNIVERSITY OF MARYLAND BALTIMORE
• 依托单位国家: 美国
• 财政年份: 2012
• 资助国家: 美国
• 起止时间: 2012-08-15 至 2015-05-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8530142
• 关键词: Activities of Daily Living; Acute; Adult; Aerobic; Aerobic Exercise; Affect; Age; Aging; American; Biological Assay; Biology; Blood Circulation; Blood Vessels; Bone Marrow; CD34 gene; Cardiovascular Diseases; Cathepsin L; Cell Count; Cell physiology; Data; Development; Diabetes Mellitus; Educational process of instructing; Elderly; Endothelium; Erythropoietin; Exercise; Functional disorder; Gene Expression; Growth; Health; Hyperglycemia; Immigration; K-Series Research Career Programs; Lead; Learning; Matched Group; Measurement; Measures; Mediating; Mentors; Methods; Molecular; NADPH Oxidase; Non-Insulin-Dependent Diabetes Mellitus; Obesity; Overweight; Patients; Peptide Hydrolases; Reactive Oxygen Species; Research; Research Project Grants; Research Training; Skeletal Muscle; Stem cells; Stromal Cell-Derived Factor 1; Testing; Therapeutic; Therapeutic Intervention; Time; Tissues; Training; Translating; Translational Research; Tube; Vascular Endothelial Growth Factors; angiogenesis; cardiovascular risk factor; career; cell motility; design; drug discovery; impaired glucose tolerance; improved; middle age; migration; novel; patient oriented; repaired; research study; response; sedentary; skills

DESCRIPTION (provided by applicant): Endothelial progenitor cell (EPC) dysfunction may contribute to vascular dysfunction in type 2 diabetes (T2DM) and aging because EPCs are progenitor cells that participate in vascular growth and repair. EPCs may be dysregulated in older age and T2DM by reduced mobilization from bone marrow and impaired function once in the circulation. My preliminary data suggest that aerobic exercise training may increase EPC and vascular function in T2DM, but that the effects may be reduced in older age. This study tests the hypothesis that reduced EPC mobilization and function adversely affect vascular function in T2DM, and that and that there are age-associated differences in the effects of AEX training on EPC mobilization and function in T2DM, which will affect AEX-induced changes in angiogenesis and endothelial vasoreactivity. This will be accomplished by specific aims that 1) Determine the effects of 6-month aerobic exercise training on EPC number and EPC mobilization factor expression in older subjects with T2DM compared middle-aged T2DM subjects and normal controls; and 2) Determine the effects of 6-month aerobic exercise training on mechanisms regulating EPC function and migration in older subjects with T2DM compared middle-aged T2DM subjects and normal controls. I will study sedentary, overweight/obese (BMI >25 kg/m2), middle-aged (50-65 yrs) and older (65-80 yrs) adults with T2DM and an age- and BMI- matched group of healthy controls. All subjects will be studied before and after 6-months of aerobic exercise training. An acute bout of exercise will be used to assess EPC mobilization at each time point to determine whether EPC mobilization is reduced in older vs. middle-aged T2DM subjects and normal controls, and also whether aerobic exercise training improves EPC mobilization. In the same subjects, ex vivo EPC tube formation, migration, and gene expression will be measured to determine whether specific markers of EPC function are reduced in middle-aged and older T2DM compared to controls and are improved with exercise training. Endothelial vasoreactivity and skeletal muscle capillarization will be measured to determine whether increases in EPC mobilization and function are associated with improved vascular function in T2DM and whether this differs between older and middle-aged T2DM subjects. This mentored, patient-oriented translational research study will provide me with the training to determine mechanisms of EPC dysfunction at the molecular and cellular level, and translate those findings to tissue (skeletal muscle capillarization) and the whole body level (endothelial vasoreactivity). Results of this study will enhance our understanding of EPC and vascular dysfunction and may lead to therapeutic and pharmacologic strategies to reduce vascular dysfunction in T2DM. This Paul B. Beeson Patient-Oriented Career Development Award will allow me to transition to an independent research career and become a leader in translational research in vascular biology in aging and diabetes.

描述（由申请人提供）：内皮祖细胞（EPC）功能障碍可能导致2型糖尿病（T2DM）和衰老中的血管功能障碍，因为EPC是参与血管生长和修复的祖细胞。在老年和 T2DM 中，EPC 可能会因骨髓动员减少和进入循环后功能受损而失调。我的初步数据表明，有氧运动训练可能会增加 T2DM 患者的 EPC 和血管功能，但随着年龄的增长，其效果可能会减弱。本研究检验了以下假设：EPC 动员和功能减少会对 T2DM 患者的血管功能产生不利影响，并且 AEX 训练对 T2DM 患者 EPC 动员和功能的影响存在年龄​​相关差异，这将影响 AEX 诱导的血管功能变化。血管生成和内皮血管反应性。这将通过以下具体目标来实现： 1) 与中年 T2DM 受试者和正常对照相比，确定 6 个月有氧运动训练对老年 T2DM 受试者 EPC 数量和 EPC 动员因子表达的影响； 2) 与中年 T2DM 受试者和正常对照相比，确定 6 个月有氧运动训练对老年 T2DM 受试者 EPC 功能和迁移调节机制的影响。 我将研究久坐、超重/肥胖（BMI > 25 kg/m2）、中年（50-65 岁）和老年（65-80 岁）患有 T2DM 的成年人以及年龄和 BMI 匹配的健康对照组。所有科目都将在 6 个月的有氧运动训练之前和之后进行研究。将使用急性运动来评估每个时间点的 EPC 动员，以确定老年 T2DM 受试者和正常对照组的 EPC 动员是否减少，以及有氧运动训练是否改善 EPC 动员。在同一受试者中，将测量离体 EPC 管的形成、迁移和基因表达，以确定与对照组相比，中老年 T2DM 中 EPC 功能的特定标志物是否减少，并通过运动训练得到改善。将测量内皮血管反应性和骨骼肌毛细血管化，以确定 EPC 动员和功能的增加是否与 T2DM 患者血管功能的改善相关，以及老年和中年 T2DM 受试者之间是否存在差异。 这项以患者为指导的转化研究将为我提供培训，以确定分子和细胞水平上的 EPC 功能障碍机制，并将这些发现转化为组织（骨骼肌毛细血管化）和全身水平（内皮血管反应性）。这项研究的结果将增强我们对 EPC 和血管功能障碍的理解，并可能导致制定减少 T2DM 血管功能障碍的治疗和药理学策略。 Paul B. Beeson 以患者为导向的职业发展奖将使我能够过渡到独立研究职业，并成为衰老和糖尿病血管生物学转化研究的领导者。