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

描述(申请人提供)：内皮祖细胞(EPC)功能障碍可能导致2型糖尿病(T2 DM)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2型糖尿病患者中，由于骨髓动员减少和循环功能受损，内皮祖细胞可能处于失调状态。我的初步数据表明，有氧运动训练可能会增加T2 DM患者的EPC和血管功能，但这种影响在老年可能会减弱。本研究验证了以下假设：T2 DM患者EPC动员和功能降低会对血管功能产生不利影响，并且AEX训练对T2 DM患者EPC动员和功能的影响存在年龄相关性差异，这将影响AEX诱导的血管生成和内皮血管反应性的变化。这将通过特定的目标来实现：1)确定6个月有氧运动训练对老年T2 DM患者与中年T2 DM患者和正常对照组EPC数量和EPC动员因子表达的影响；2)确定6个月有氧运动训练对老年T2 DM患者EPC功能和迁移调节机制的影响。 我将研究久坐不动的超重/肥胖(BMI&GT；25公斤/平方米)、中年(50-65岁)和老年(65-80岁)T2 DM患者，以及一组年龄和BMI匹配的健康对照组。所有受试者将在为期6个月的有氧运动训练之前和之后进行研究。在每个时间点，将使用一次急性运动来评估EPC动员，以确定老年与中年T2 DM患者和正常对照组的EPC动员是否减少，以及有氧运动训练是否改善EPC动员。在相同的受试者中，将测量体外EPC管的形成、迁移和基因表达，以确定与对照组相比，中老年T2 DM患者EPC功能的特定标记物是否减少，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T2 DM患者血管功能的改善有关，以及这在老年和中年T2 DM受试者之间是否有所不同。 这项有指导的、以患者为导向的转化性研究将为我提供培训，以在分子和细胞水平确定EPC功能障碍的机制，并将这些发现转化为组织(骨骼肌毛细化)和全身水平(内皮血管反应性)。这项研究的结果将加深我们对EPC和血管功能障碍的理解，并可能导致减少T2 DM血管功能障碍的治疗和药物策略。保罗·B·比森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生涯，并成为衰老和糖尿病血管生物学翻译研究的领导者。

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.