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: 8368174
• 负责人: Steven J Prior
• 金额: $ 18.22万
• 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 2015-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8368174
• 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. PUBLIC HEALTH RELEVANCE: The research project in this K23 BCDA is designed to discover mechanisms underlying endothelial progenitor cell (EPC) and vascular dysfunction in type 2 diabetes and aging. Further, it will determine whether exercise training-induced increases in EPC mobilization contribute to improved vascular function in middle-aged and older adults with type 2 diabetes. The identification of the mechanisms of EPC and vascular dysfunction would have a significant impact on the millions of older Americans with T2DM, as these mechanisms can be targeted for drug discovery or other therapeutic interventions to reduce risk for cardiovascular complications.

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. PUBLIC HEALTH RELEVANCE: The research project in this K23 BCDA is designed to discover mechanisms underlying endothelial progenitor cell (EPC) and vascular dysfunction in type 2 diabetes and aging. Further, it will determine whether exercise training-induced increases in EPC mobilization contribute to improved vascular function in middle-aged and older adults with type 2 diabetes. The identification of the mechanisms of EPC and vascular dysfunction would have a significant impact on the millions of older Americans with T2DM, as these mechanisms can be targeted for drug discovery or other therapeutic interventions to reduce risk for cardiovascular complications.