Adiponectin and Endothelial Dysfunction in Adolescents

拟议的K23职业发展和研究计划将为EdmondP做准备。韦翰111，医学博士， 作为一名专注于传统和非传统作用的独立临床研究人员，从事富有成效的职业生涯 血管功能障碍中的心血管危险因素经常出现在超重和肥胖的青少年中。 候选人寻求将他在儿科、内科和内分泌学方面的独特培训结合起来，以 研究脂联素多聚体、循环祖细胞数量和功能之间的关系，以及 青少年的内皮功能。应聘者将完成研究设计方面的正式教学培训， 生物统计学和公共卫生，获得公共卫生硕士学位。他将整合这间教室 在一个不同的团队的指导下完成多学科研究方案的培训 导师，每个人都有出色的研究和培训记录。 拟议的研究将检验这一假设，即在青少年中，脂联素(特别强调 高分子量[HMW]亚型)导致内皮功能障碍，部分是通过其对 循环祖细胞(CPC)的数量和功能。为了检验这一假设，应聘者将测量 传统的心血管危险因素(血压、腰围、血脂、血糖)、胰岛素抵抗 (在口服葡萄糖耐量试验中使用葡萄糖和胰岛素)、炎症细胞因子、脂联素 多聚体、CPC数量(CD34细胞通过流式细胞术测定)和流式细胞仪的FMD 30名正常体重、30名超重和100名11-18岁肥胖青少年的肱动脉。基线衡量标准 将60名肥胖青少年在12周后重复参加以家庭为基础的、有条理的 体重管理计划。此外，体外CPC研究(集落形成单位[CFU- Hill]和在小管形成试验中的CPC掺入)将在从30名肥胖者分离的细胞上进行 患有代谢综合征(METS)的青少年(14-18岁)和30名正常体重的儿童。最后，在一个 对20名青少年(肥胖组10名，正常体重组10名)进行第二次小管形成试验 在人重组脂联素存在的情况下，测定脂联素对CP功能的影响。 相关性(请参阅说明)： 肥胖青少年罹患包括糖尿病在内的重大健康问题的风险增加 糖尿病、高胆固醇和高血压；每一种都与 患心血管疾病的风险。脂联素，一种由脂肪细胞释放的激素，可能在 早期的血管变化最终会导致心脏病。

The proposed K23 career development and research plans will prepare EdmondP. Wickham 111, M.D., for a productive career as an independent clinicalinvestigator focusing on the role of traditional andnon-traditional cardiovascular risk factors in the vascular dysfunction frequently present in overweight and obese adolescents. The candidate seeks to combine his unique training in Pediatrics, Internal Medicine, and Endocrinology to examine the relationships among adiponectin multimers, circulating progenitor cell number and function, and endothelial function in adolescents. The candidate will complete formal didactic training in study design, biostatistics, and publichealth resulting in a Masters of Public Health degree. He will integrate this classroom training with the completion of a multi-disciplinary research protocol under the guidance of a diverse team of mentors, each with exceptional research and training records. The proposed studies will test the hypothesis that in adolescents, adiponectin (with particular emphasis on the high molecularweight [HMW]isoform) contributes to endothelial dysfunction,in part through its effects on circulating progenitor cell (CPC)number and function. To test this hypothesis, the candidate will measure traditional cardiovascular risk factors (blood pressure, waist circumference, lipids,glucose), insulin resistance (using glucose and insulinvalues during an oral glucose tolerance test), inflammatory cytokines,adiponectin multimers, CPC number (CD34+ cells determined by flow cytometry), and flow-mediateddilation (FMD) of the brachial artery in 30 normal-weight, 30 overweight, and 100 obese adolescents ages 11-18. Baseline measures will be repeated in 60 of the obese adolescents after 12-weeks of participation in a family-based, structured weight management program. Additionally, in vitro CPC studies (quantificationof colony forming units [CFU- Hill] and CPC incorporation during a tubule formation assay) will be performed on cells isolated from 30 obese adolescents (ages 14-18) with the metabolic syndrome (MetS) and 30 normal-weight children. Finally, in a subset of 20 adolescents (10 obese-MetS, 10 normal-weight), a second tubule formation assay will beperformed in the presence of human recombinant adiponectin to determine the effects of adiponectin on CPCfunction. RELEVANCE (See instructions): Obese adolescents are at increased risk of developing significant health problems including diabetes mellitus, elevated cholesterol, and elevated blood pressure; each of which is associated with an increased risk of cardiovascular disease. Adiponectin, a hormone released by fat cells, may play an important role in the early blood vessel changes that ultimately lead to heart disease.