VitaminA and Sickle Cell Disease:Improving Suboptimal Status with Supplementation

描述（由申请人提供）：Kelly Dougherty，Ph.D.，是宾夕法尼亚大学佩雷尔曼医学院和费城儿童医院（CHOP）的儿科助理教授。Doughnut博士提出了一个全面的跨学科培训计划，将为她提供必要的技能和经验，以发展成为一个独立的学术以患者为导向的儿科研究调查员，专注于解决营养和身体活动相关的问题影响镰状细胞病（SCD）儿童的临床试验。她的职业发展将由营养，生长，慢性疾病，稳定同位素评估，眼科，流行病学/研究设计和生物统计学方面的研究人员组成的团队指导。她的主要导师弗吉尼亚·斯塔林斯医学博士在过去的27年里，他进行了儿科临床营养和慢性疾病研究，并担任CHOP教师发展办公室主任，在支持初级教师发展为独立的NIH资助的临床研究人员方面享有盛誉。拟议的指导经验将发生在该国最优秀的营养和SCD临床研究环境之一。Doughnut博士的培训将包括研究设计、生物统计学、研究伦理和稳定同位素方面的高级正式课程。这种培训对于巩固营养基础至关重要， SCD研究知识，她在她的博士后奖学金和宾夕法尼亚大学硕士转化研究（MTR）论文工作，并准备她为未来的R01提交进行营养干预研究SCD儿童获得。拟议的研究项目将重点关注次优维生素A（vit A）状态，这种状态在患有SS型镰状细胞病（SCD-SS）的儿童中普遍存在，并与住院和不良生长和血液学状态相关。在患有SCD-SS的儿童中的初步数据显示，按健康儿童推荐的剂量补充维生素A未能改善维生素A状态，导致住院，生长或暗适应没有变化。这表明维生素A的需求增加，最有可能是由于慢性炎症，维生素A摄入量低和可能的粪便或尿液损失。在SCD-SS受试者中优化维生素A状态所需的维生素A剂量尚不清楚。拟议的研究将在66名9至18岁的SCD-SS儿童中确定维生素A补充剂量（3000和5000 IU/d）与安慰剂相比的安全性和有效性，并测试维生素A补充对关键功能和临床结局的影响。关键的安全性指标是同时升高血清视黄醇（年龄特异性）和肝功能检查（3x年龄特异性）。使用最先进的稳定同位素方法，通过肝脏vtA储存的补充来评价功效。在SCD-SS中，使用氘代视黄醇稀释技术在3个月干预前后评估全身维生素A池大小和肝脏维生素A浓度。将在类似的健康受试者中评估基线维生素A状态作为对照组。维生素A治疗在安全和经济地改善SCD患者的并发症和生活质量方面具有很大的前景。迫切需要设计良好的试验来确定维生素A补充剂的临床影响，这项研究是下一步。

DESCRIPTION (provided by applicant): Kelly Dougherty, Ph.D., is an Assistant Professor of Pediatrics at University of Pennsylvania (UPenn) Perelman School of Medicine and The Children's Hospital of Philadelphia (CHOP). Dr. Dougherty proposes a comprehensive, interdisciplinary training program that will provide her with the skills and experience necessary to develop into an independent academic patient-oriented investigator in pediatric research, focusing on clinical trials addressing nutrition- and physical activity-related issues affecting children with sickle cell disease (SCD). Her career development will be guided by an accomplished team of investigators in nutrition, growth, chronic disease, stable isotope assessment, ophthalmology, epidemiology / study design and biostatistics. Her primary mentor, Virginia Stallings, M.D. has conducted pediatric clinical nutrition and chronic disease research for the last 27 years and as Director of the Office of Faculty Development at CHOP, has an superb reputation for supporting the development of junior faculty into independent, NIH-funded, clinical investigators. The proposed mentored experience will take place in one of the most outstanding nutrition and SCD clinical research environments in the country. Dr. Dougherty's training will include advanced formal coursework in research design, biostatistics, research ethics and stable isotopes. This training is crucial to build upon the foundations of nutrition and SCD research knowledge that she obtained during her postdoctoral fellowship and UPenn Masters in Translational Research (MTR) thesis work and to prepare her for future R01 submissions to conduct nutrition intervention studies in children with SCD. The proposed research project will focus on suboptimal vitamin A (vit A) status which is prevalent in children with type SS sickle cell disease (SCD-SS) and associated with hospitalizations and poor growth and hematological status. The preliminary data in children with SCD-SS show that vit A supplementation at the dose recommended for healthy children failed to improve vit A status, resulting in no change in hospitalizations, growth or dark adaptation. This indicates an increased vit A requirement most likely due to chronic inflammation, low vit A intake and possible stool or urine loss. The dose of vit A needed to optimize vit A status in subjects with SCD-SS is unknown. The proposed research study will establish the safety and efficacy of vit A supplementation doses (3000 and 5000 IU/d) compared to placebo over 3 months in 66 children with SCD-SS, age 9-to 18-yrs and test the impact of vit A supplementation on the key functional and clinical outcomes. The key safety measures are concurrently elevated serum retinol (age specific) and liver function tests (3x age specific). Efficacy is evaluated by repletion of liver vt A stores using state of the art stable isotope methods. In SCD-SS, total body vit A pool size and liver vit A concentration are assessed before and after the 3 month intervention using the deuterated-retinol-dilution technique. Baseline vit A status will be assessed in similar healthy subjects as a comparison group. Vit A therapy has great promise to safely and economically improve complications and quality of life for patients with SCD. Well-designed trials are urgently needed to determine the clinical impact of vit A supplementation and this study is the next step.