Vitamin A Status and its Relationship to S. mansoni Infection Intensity and Environmental Enteric Dysfunction in Preschool-Aged Children Receiving Treatment for Schistosomiasis in Uganda

项目摘要/摘要 这项建议的总体目标是促进我们对维生素A缺乏在 血吸虫病的发病机制与环境肠道功能障碍(EED)及推进事业 候选人的发展。认识维生素A缺乏在发病机制中的作用 肠道血吸虫病的控制将为以营养为基础的干预提供机会，以减少与感染相关的 发病率。在低收入和中等收入国家，营养不良和营养不良的重叠负担 感染对婴儿和儿童有重大的健康后果，包括线性发育受损和 发育迟缓。发育迟缓影响着生活在LMIC中的三分之一的儿童，并可能导致终身影响教育 妇女的结果、经济生产力和生育结果。肠道维生素A缺乏症 血吸虫病和EED都会导致儿童营养不良和发育迟缓，并可能有共同的 通过肠道屏障功能障碍伴随的全身免疫反应激活的机制。 来自动物模型和人类的研究为这些侮辱在受损的人中的作用提供了科学前提 线性增长。最近开发的一种炎症调节策略允许测定维生素A 感染或炎症患者的状况，但没有研究检查调整后的维生素A 在人类血吸虫病或EED的背景下的地位。拟议的研究将充分利用- 一项由美国国立卫生研究院资助的随机对照II期试验的特征样本和临床数据(R01 吡喹酮(PZQ)治疗N=300名4岁以下儿童曼氏血吸虫 乌干达阿尔伯特湖地区的感染。家长试验假设关键疾病与 血吸虫病(营养不良、炎症贫血和直线生长迟缓)在一定程度上是由EED引起的 从而导致吸收不良和全身免疫激活。拟议的研究将增加 从父母试验中收集的样本中维生素A的测量，以检查通过 炎症调整的维生素A缺乏导致EED和血吸虫病相关的发病率。这个 拟议的研究将1)检查调整后的维生素A状态与曼氏葡萄球菌之间的关系 在基线访问中收集的感染强度和免疫反应标记物，以及2)评估 维生素A状态与EED生物标志物在基线和纵向上的关系 PZQ治疗。这项工作将解决关于维生素A状态在 曼氏葡萄球菌感染背景下EED的病理生理学及其对治疗效果的影响。此外， 拟议的培训计划将促进候选人在a)建筑专业的职业发展 在血吸虫病免疫发病机制和EED方面的物质专门知识，b)在以下方面获得研究经验 在赞助商的监督下在脆弱人群中实施随机对照试验， 以及c)扩大方法学能力，包括纵向数据分析。

PROJECT SUMMARY/ABSTRACT The overall goals of this proposal are to advance our understanding of the role of vitamin A deficiency in the pathogenesis of schistosomiasis and environmental enteric dysfunction (EED) and to advance the career development of the candidate. Understanding the mechanistic role of vitamin A deficiency in the pathogenesis of intestinal schistosomiasis will offer opportunities for nutrition-based interventions to reduce infection-related morbidity. In low- and middle-income countries (LMICs), the overlapping burdens of undernutrition and infection have significant health consequences for infants and children, including impaired linear growth and stunting. Stunting affects a third of children living in LMICs and can lead to life-long impact on educational outcomes, economic productivity, and birth outcomes for women. Vitamin A deficiency, intestinal schistosomiasis, and EED all contribute to childhood undernutrition and stunting and likely share common mechanisms through intestinal barrier dysfunction with concomitant activation of systemic immune responses. Studies from both animal models and humans provide scientific premise for the role of these insults in impaired linear growth. A recently developed inflammation-adjustment strategy allows for the determination of vitamin A status among individuals with infection or inflammation, but no studies have examined adjusted vitamin A status in the context of human schistosomiasis or EED. The proposed research will leverage the well- characterized samples and clinical data from an ongoing NIH-funded randomized, controlled phase II trial (R01 HD095562) of praziquantel (PZQ) treatment in N = 300 children under age four with Schistosoma mansoni infection in the Lake Albert region of Uganda. The parent trial hypothesizes that key morbidities related to schistosomiasis (undernutrition, anemia of inflammation, and linear growth stunting) are in part driven by EED with consequent malabsorption and systemic immune activation. The proposed research will add measurements of vitamin A in samples collected from the parent trial to examine mechanisms through which inflammation-adjusted vitamin A deficiency contributes to EED and schistosomiasis-related morbidity. The proposed research will 1) examine the relationships between adjusted vitamin A status and S. mansoni infection intensity and immunologic response markers collected at the baseline visit and 2) assess the relationships between vitamin A status and EED biomarkers both at baseline and longitudinally in response to PZQ treatment. This work will address innovative hypotheses regarding the role of vitamin A status in the pathophysiology of EED in the context of S. mansoni infection and its impact on treatment efficacy. Further, the proposed training plan will advance the career development of the candidate with respect to a) building subject matter expertise in the immunopathogenesis of schistosomiasis and EED, b) gaining research experience in the implementation of randomized controlled trials in vulnerable populations under a sponsor’s supervision, and c) expanding methodological capabilities to include longitudinal data analysis.