Validation of Circulating Endothelial Cells and Microparticles in Youth

描述（由申请人提供）：儿童慢性疾病生物标志物的验证是至关重要的，特别是在儿童肥胖研究的新兴领域。由于心血管疾病（CVD）是一个随时间累积发生的过程，识别最早的迹象以便尽早干预可能对减缓其进展有很大影响。挑战在于确定哪些肥胖青少年有早期血管问题。由于血管内皮在动脉粥样硬化的起源中起着重要作用，因此观察血管内皮损伤的迹象是一种合理的方法。然而，准确量化儿童内皮健康状况已被证明是一项重大挑战。肱动脉血流介导扩张（FMD）是量化儿童内皮健康最常用的方法。然而，这项技术并不广泛适用，因为它需要专门的设备和训练有素的技术人员，而且结果可能变化很大。更直接的内皮细胞生物学测量，如循环内皮细胞（CEC）和内皮微粒（EMP），可以更精确地描述内皮的状态，并可以识别高风险个体。尽管在成人中得到了验证，CEC和EMP尚未在青少年中得到正式评估。我们在这项研究中的主要重点是评估CEC和EMP作为心血管疾病风险的生物标志物，在整个儿童和青少年肥胖的范围内，目的是验证CEC和EMP在儿科研究中的应用。我们提出了一个强有力的研究设计，采用三层方法来验证这些生物标志物：1)评估CEC和EMP与心血管疾病危险因素的相关性，以及内皮功能（FMD）和亚临床动脉粥样硬化（颈动脉内膜-中膜厚度）的测量；2)评估重度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；3)对CEC和EMP的可重复性进行纵向评估，为使用这些终点的未来儿科研究设计提供信息。

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.