Validation of Circulating Endothelial Cells and Microparticles in Youth

描述(由申请人提供)：儿童慢性病生物标记物的验证至关重要，特别是在儿童肥胖研究的新兴领域。由于心血管疾病(CVD)是一个随着时间的积累而发生的过程，识别最早的迹象以便更早地进行干预可能会对减缓其进展产生很大影响。挑战是确定哪些肥胖青年早期有血管问题。寻找血管内皮细胞的损伤迹象是一个合理的方法，因为它在动脉粥样硬化的起源中起着突出的作用。然而，准确量化儿童的内皮健康已被证明是一项重大挑战。肱动脉血流介导的扩张(FMD)是最常用的方法来量化儿童的内皮健康。然而，这项技术并不广泛适用，因为它需要专门的设备、训练有素的技术人员，而且结果可能会有很大的变数。更直接的内皮细胞生物学指标，如循环内皮细胞(CEC)和内皮微粒(EMP)，可能在表征内皮状态方面提供更高的精确度，并可能识别高危个体。尽管在成年人中得到了验证，CEC和EMP还没有在年轻人中得到正式评估。我们在这项研究中的主要焦点将是评估CEC和EMP作为心血管疾病风险的生物标志物，贯穿儿童和青少年肥胖症的整个谱系，目的是验证CEC和EMP在儿科研究中的使用。我们提出了一个稳健的研究设计，采用三层方法来验证这些生物标志物：1)同时评估CEC和EMP与心血管危险因素以及内皮功能(FMD)和亚临床动脉粥样硬化(颈动脉内膜中层厚度)的测量之间的关系；2)评估极端肥胖青少年接受选择性、临床指示的减肥手术后CEC和EMP的变化；以及3)对CEC和EMP的可重复性进行纵向评估，以便为使用这些终点的未来儿科研究的设计提供信息。 公共卫生相关性：该项目将评估两种新的血管损伤标志物在不同体脂水平的儿童和青少年中的有效性，以评估它们在儿科临床研究中的潜在有用性。

DESCRIPTION (provided by applicant): Validation of chronic disease biomarkers in children is of paramount importance especially in the burgeoning arena of pediatric obesity research. Because cardiovascular disease (CVD) is a cumulative process occurring over time, identifying the earliest signs in order to intervene sooner may have a large impact on slowing its progression. The challenge is identifying which obese youth have early vascular problems. Looking to the vascular endothelium for signs of damage is a reasonable approach because of its prominent role in the origins of atherosclerosis. However, accurately quantifying endothelial health in children has proven to be a major challenge. Brachial artery flow-mediated dilation (FMD) is the most commonly-used method to quantify endothelial health in children. However, this technique is not widely applicable because it requires specialized equipment, a highly-trained technician, and results can be highly variable. More direct measures of endothelial cell biology, such as circulating endothelial cells (CEC) and endothelial microparticles (EMP), may offer greater precision in characterizing the state of the endothelium and may identify high-risk individuals. Despite being validated in adults, CEC and EMP have not been formally evaluated in youth. Our primary focus in this study will be the evaluation of CEC and EMP as biomarkers of CVD risk, throughout a spectrum of adiposity in children and adolescents, with a goal of validating CEC and EMP for use in pediatric research studies. We propose a robust study design with a three-tiered approach toward validating these biomarkers: 1) evaluation of the association of CEC and EMP concurrently with CVD risk factors and measures of endothelial function (FMD) and sub-clinical atherosclerosis (carotid intima-media thickness), 2) evaluation of the change in CEC and EMP in response to substantial weight loss in extremely obese adolescents undergoing elective, clinically- indicated bariatric surgery, and 3) longitudinal assessment of the reproducibility of CEC and EMP to inform the design of future pediatric studies using these endpoints. PUBLIC HEALTH RELEVANCE: This project will evaluate the validity of two new markers of vascular damage in children and adolescents with varying levels of body fat in order to assess their potential usefulness in pediatric clinical research studies.