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）和衰老的血管功能障碍，因为EPC是参与血管生长和修复的祖细胞。 EPC在老年年龄和T2DM中可能失调，通过在循环中减少骨髓动员和功能受损。我的初步数据表明，有氧运动训练可能会增加T2DM中的EPC和血管功能，但可能会降低效果。这项研究检验了以下假设：降低EPC动员和功能对T2DM中的血管功能不利，并且在AEX培训对T2DM中EPC动员和功能的影响中存在与年龄相关的差异，这将影响AEX诱导的血管生成和内皮血管生成的变化。这将通过特定目的来完成，即1）确定6个月的有氧运动训练对T2DM老年受试者EPC数量和EPC动员因子表达的影响，比较了中年T2DM受试者和正常对照； 2）确定6个月有氧运动训练对调节T2DM较老受试者的EPC功能和迁移的机制的影响，比较了中级T2DM受试者和正常对照。 我将研究久坐的，超重/肥胖（BMI> 25 kg/m2），中年（50 - 65年）和年龄较大（65-80岁）的成年人，具有T2DM和年龄和BMI-I-I-I-I-I-I-BMI-I-I-MI-I-Healthy对照组。所有受试者将在有氧运动训练6个月之前和之后进行研究。急性锻炼将用于评估每个时间点的EPC动员，以确定在较旧的与中年T2DM受试者和正常对照中的EPC动员是否减少，以及有氧运动训练是否可以改善EPC的动员。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，在中年和较旧的T2DM中，EPC功能的特定标记是否降低，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管化，以确定EPC动员和功能的增加是否与T2DM中的血管功能改善有关，以及在老年和中年T2DM受试者之间是否有所不同。 这项受到指导的，以患者为导向的转化研究将为我提供训练，以确定EPC功能障碍在分子和细胞水平上的机制，并将这些发现转化为组织（骨骼肌毛细血管化）和整个身体水平（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，并可能导致治疗和药理策略减少T2DM中血管功能障碍。保罗·B·比森（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的研究职业，并成为衰老和糖尿病血管生物学转化研究的领导者。