Metabolic Syndrome after Pediatric Liver Transplant: Causes and Consequences

描述(由申请人提供)：这份K23将支持艾米丽·R·佩里托医学博士的职业发展，她是一名儿科肝病和胃肠病专家。她的目标是成为一名独立的临床研究员，专注于改善儿童肝移植接受者的长期结果。移植后代谢综合征(PTMS)是成人肝移植后长期发病率和死亡率的主要因素。在肝移植后的儿童中，代谢综合征的个别组成部分--包括高血压、血脂异常和糖耐量异常--在年龄、性别和肥胖程度上比预期的更常见。但它们作为代谢综合征的聚集性及其对长期移植物和患者健康的影响尚未被研究。这项研究的目的是调查儿科肝移植受者PTMS的危险因素、后果和治疗策略。这项调查集中在两个可改变的PTMS原因：肥胖和钙调神经磷酸酶抑制剂毒性。钙调神经磷酸酶抑制剂是实体器官移植后维持免疫抑制的主要药物。它们的副作用包括高血压、血脂异常和糖耐量异常--但不包括肥胖。在K23的支持下，佩里托博士将建立两个儿科肝脏移植受者的预期队列-移植后晚期队列，她将研究流行的PTM及其进展，以及移植前的试点队列，她将调查事件PTMS。对晚期队列的基线横断面研究将使Perito博士能够确定PTMS的患病率及其与早期心血管疾病和NAFLD的关联(目标1)。这一队列将被前瞻性地跟踪调查钙调神经磷酸酶抑制剂剂量调整对PTMS、早期心血管疾病和NAFLD的影响(AIM 2)。佩里托博士还将跟踪肝移植前儿童的一小部分试点队列，以确定新发的儿科PTM的风险因素(AIM 3)。这项试点将专注于肥胖和皮质类固醇暴露，以及钙调神经磷酸酶抑制剂的毒性。这些研究将指导未来对筛查和管理策略的干预研究，以减少儿童肝移植受者PTMS相关的发病率。佩里托博士的指导团队和培训计划将促进这项研究和她的职业发展。该奖项将为佩里托博士提供以下方面的额外培训：(1)高级统计学和流行病学；(2)肥胖、胰岛素抵抗和代谢综合征的科学；(3)研究队列的开发和管理；以及(4)干预性研究的设计。儿科肝病学家和临床研究员菲利普·罗森塔尔博士是主要导师。儿科内分泌学家罗伯特·卢斯蒂格博士将提供代谢综合征方面的专业知识。生物统计学家大卫·格里登博士将提供纵向数据分析方面的指导。心血管流行病学家Kirsten Bibbins-Domingo博士将指导年轻人的心血管风险评估。该团队的多学科专业知识将使佩里托博士能够建立一个独特的独立研究计划，致力于改善儿科肝脏移植后的长期结果。

DESCRIPTION (provided by applicant): This K23 will support the career development of Emily R. Perito, MD, a pediatric hepatologist and gastroenterologist. Her goal is to be an independent clinical investigator focused on improving long-term outcomes in pediatric liver transplant recipients. Post-transplant metabolic syndrome (PTMS) is a major contributor to long-term morbidity and mortality after liver transplant in adults. In children after liver transplant, individual components of metabolic syndrome-including hypertension, dyslipidemia, and glucose intolerance-are more common than expected for age, gender, and degree of obesity. But their clustering as metabolic syndrome and their impact on long-term graft and patient health has not been studied. The goal of this research is to investigate risk factors for, consequences of, and strategies to treat PTMS in pediatric liver transplant recipients. The investigation focuses on two modifiable causes of PTMS: obesity and calcineurin- inhibitor toxicity. Calcineurin-inhibitors are the mainstay of maintenance immunosuppression after solid-organ transplant. Their side effects include hypertension, dyslipidemia, and glucose intolerance-but not obesity. With the support of this K23, Dr. Perito will establish two prospective cohorts of pediatric liver transplant recipient-a late post-transplant cohort in which she will study prevalent PTMS and its progression, and a pilot cohort followed from pre-transplant in which she will investigate incident PTMS. A baseline cross-sectional study of the late cohort will allow Dr. Perito to define the prevalence of PTMS and its association with early cardiovascular disease and NAFLD (Aim 1). This cohort will be followed prospectively to investigate the impact of calcineurin-inhibitor dose modifications on PTMS, early cardiovascular disease, and NAFLD (Aim 2). Dr. Perito will also follow a small pilot cohort of children from prior to liver transplant, to identify risk factors for new- onset pediatri PTMS (Aim 3). This pilot will focus on obesity and corticosteroid exposure, as well as calcineurin-inhibitor toxicity. These studies will guide future interventional research on screenin and management strategies to reduce PTMS-related morbidity in pediatric liver transplant recipients. Dr. Perito's mentoring team and training plan will facilitate this research and her career development. This award will provide Dr. Perito with additional training in: (1) advanced statistics and epidemiology; (2) the science of obesity, insulin resistance, and metabolic syndrome; (3) development and management of research cohorts; and (4) design of interventional studies. Dr. Philip Rosenthal, a pediatric hepatologist and clinical researcher, is the primary mentor. Dr. Robert Lustig, a pediatric endocrinologist, will provide expertise on metabolic syndrome. Dr. David Glidden, a biostatistician, will provide mentoring on longitudinal data analysis. Dr. Kirsten Bibbins-Domingo, a cardiovascular epidemiologist, will mentor on cardiovascular risk assessment in young adults. The multi-disciplinary expertise of this team will allow Dr. Perito to build a unique independent research program dedicated to improving long-term outcomes after pediatric liver transplant.