VitaminA and Sickle Cell Disease:Improving Suboptimal Status with Supplementation

简介(申请人提供)：Kelly Dougherty博士，宾夕法尼亚大学佩雷尔曼医学院和费城儿童医院儿科学助理教授。Dougherty博士提出了一个全面的跨学科培训计划，该计划将为她提供必要的技能和经验，使她能够发展成为儿科研究中以患者为中心的独立学术研究员，专注于解决影响镰状细胞病(SCD)儿童的营养和体力活动相关问题的临床试验。她的职业发展将由一支在营养、生长、慢性病、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经验丰富的研究团队指导。她的主要导师，弗吉尼亚·斯塔林斯医学博士，在过去的27年里一直从事儿科临床营养和慢性病研究，并作为CHOP学院发展办公室的主任，以支持初级教师发展为独立的、由NIH资助的临床研究人员而享有极高的声誉。建议的指导体验将在该国最优秀的营养和SCD临床研究环境之一进行。多尔蒂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。这项培训对于建立营养和营养基础至关重要 她在博士后期间和宾夕法尼亚大学翻译研究硕士(MTR)论文工作期间获得的SCD研究知识，并为她未来的R01论文提交做好准备，以对SCD儿童进行营养干预研究。拟议的研究项目将集中在次优维生素A(VitA)状态，这种状态在SS镰状细胞病(SCD-SS)儿童中很常见，与住院和生长不良和血液学状况有关。SCD-SS儿童的初步数据显示，补充健康儿童推荐剂量的维生素A未能改善维生素A状态，导致住院、生长或暗适应没有改变。这表明维生素A需求量增加，很可能是由于慢性炎症、维生素A摄入量低以及可能的大便或尿失禁。SCD-SS受试者优化维生素A状态所需的维生素A剂量尚不清楚。这项拟议的研究将在9至18岁的66名SCD-SS儿童中确定补充维生素A剂量(3000和5000国际单位/天)与安慰剂相比3个月的安全性和有效性，并测试补充维生素A对关键功能和临床结果的影响。关键的安全措施是同时升高血清视黄醇(年龄特定)和肝功能测试(3倍年龄特定)。疗效是通过使用最先进的稳定同位素方法补充肝脏Vt A储备来评估的。在SCD-SS组，在干预3个月前和3个月后，使用氢化视黄醇稀释法评估全身维生素A池大小和肝脏维生素A浓度。基线维生素A状态将在类似的健康受试者中作为对照组进行评估。维生素A治疗在安全、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.