Metabolic Syndrome Following Transplant for Leukemia

描述(申请人提供)：儿童时期患有急性白血病的成年幸存者患肥胖症的频率高于预期，心血管疾病的早期死亡率高于预期，代谢综合征(MS)的风险增加，这可能在接受造血细胞移植(HCT)作为治疗一部分的个人中更为常见。这项研究的主要目的是评估青少年和青壮年因儿童恶性血液病接受HCT治疗后胰岛素抵抗和多发性硬化症的发展之间的关系，这项应用是Baker博士最近K23奖的成功进展的结果，该奖项被资助用于研究HCT后幸存者的晚期效应。这项建议的具体目的是：1)测量胰岛素抵抗(IR，正常血糖胰岛素钳)血清胰岛素、血糖和血脂；获得血压、人体测量和DEXA扫描，对190名HCT幸存者和190名对照组进行扫描；2)评估特定的HCT治疗暴露与MS发生的相关性；3)测量细胞因子、CRP和脂肪因子；4)测量内皮功能受损和亚临床心血管疾病的早期迹象；以及5)测量HCT幸存者和对照组的饮食摄入量和体力活动。这些数据将解决以下假设：a)HCT幸存者将更多地出现IR，且IR将独立于年龄而增加，且HCT后随访时间更长；b)特定的HCT治疗暴露将与生长激素缺乏和更高程度的IR相关，c)异基因HCT将与IR相关的炎症介质水平升高相关，d)患有MS的幸存者的心血管亚临床测量结果将更高，并将与全身照射暴露(TBI)有关，e)HCT幸存者的体力活动将较少，这将与脑损伤的暴露以及移植物与宿主疾病相关。这项研究提供了一个重要而令人兴奋的机会，以探索儿童癌症治疗、多发性硬化症以及与之相关的过早心血管疾病和2型糖尿病风险增加的潜在可改变的后遗症。由于HCT是一种广泛应用于白血病以及儿童和成人许多其他恶性和非恶性疾病的治疗方式，全世界每年有数千人成为幸存者，因此它是一个越来越重要的研究群体。

DESCRIPTION (provided by applicant): Adult survivors of acute leukemia in childhood have a higher than expected frequency of obesity early mortality from cardiovascular disease, and an increased risk for the metabolic syndrome (MS), and this may be more common in individuals who received hematopoietic cell transplant (HCT) as part of their therapy. The major objective of this research is to evaluate the relationship between HCT specific treatment exposures and the development of insulin resistance and the MS in adolescent and young adult survivors after HCT for treatment of hematologic malignancies in childhood, and this application is the result of the successful progression of Dr. Baker's recent K23 award, funded to study late effects in survivors after HCT. The specific aims of this proposal are: 1) to measure insulin resistance (IR, euglycemic insulin clamp) serum insulin, glucose, and lipids; to obtain blood pressure, and anthropometric measurements; and DEXA scans in 190 survivors of HCT and 190 controls; 2) evaluate the association of specific HCT treatments exposures with the development of the MS; 3) to measure cytokines, CRP and adipokines; 4) to measure early signs of impaired endothelial function and sub-clinical cardiovascular disease; and 5) to obtain measures of dietary intake and physical activity in HCT survivors and controls. These data will address the hypotheses that a) HCT survivors will be more IR, and that IR will increase independent of age with longer follow-up after HCT, b) specific HCT treatment exposures will be associated with growth hormone deficiency and higher degrees of IR, c) allogeneic HCT will be associated with higher levels of inflammatory mediators associated with IR, d) vascular measurements of sub-clinical cardiovascular changes will be higher in survivors with MS and will be associated with total body irradiation exposure (TBI), e) HCT survivors will be less physically active and this will be correlated with exposure to TBI and with having had graft vs. host disease. This research offers a significant and exciting opportunity to explore a potentially modifiable late effect of childhood cancer treatment, the MS and the associated heightened risk for premature cardiovascular disease and type 2 diabetes. Since HCT is a widely applied therapeutic modality for leukemia as well as many other malignant and non-malignant diseases in children and adults with thousands of individuals worldwide every year becoming survivors, it is an increasingly important group to study.