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

乌干达接受血吸虫病治疗的学龄前儿童维生素 A 状况及其与曼氏血吸虫感染强度和环境肠道功能障碍的关系

• 批准号: 10751105
• 负责人: Susannah Colt
• 金额: $ 7.6万
• 依托单位: RHODE ISLAND HOSPITAL
• 依托单位国家: 美国
• 财政年份: 2023
• 资助国家: 美国
• 起止时间: 2023-12-12 至 2026-12-11
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10751105
• 关键词: Address; Affect; Age; Anemia due to Chronic Disorder; Animal Model; Animals; Antibodies; Area; Biological Markers; Birth; Blood Circulation; Career Mobility; Cessation of life; Child; Child Health; Childhood; Chronic; Clinical; Clinical Data; Clinical Trials; Data; Data Analyses; Dietary intake; Dose; Economics; Education; Endotoxins; Enteral; Environmental Impact; Environmental Risk Factor; Epithelium; Equation; Face; Feces; Frequencies; Functional disorder; Funding; Goals; Goblet Cells; Growth; Growth and Development function; Health; Height; Human; IgE; Immune response; Impaired cognition; Impairment; Individual; Infant; Infection; Inflammation; Interleukin-13; Interleukin-4; Interleukin-5; Intervention; Intestinal permeability; Intestines; Knowledge; Lactulose; Leukocyte L1 Antigen Complex; Malabsorption Syndromes; Malnutrition; Mannitol; Measurement; Measures; Methodology; Modeling; Morbidity - disease rate; Mucous body substance; Nursery Schools; Nutrient; Outcome; Parasitic Diseases; Parasitic infection; Parents; Participant; Pathogenesis; Pathway interactions; Phase; Play; Praziquantel; Productivity; Randomized; Randomized, Controlled Trials; Reporting; Research; Resource-limited setting; Risk; Risk Factors; Rodent; Role; Sampling; Schistosoma mansoni; Schistosoma mansonii infection; Schistosomiasis; School-Age Population; Scientific Advances and Accomplishments; Serum; Sterility; Supervision; Training; Treatment Efficacy; Uganda; United States National Institutes of Health; Urine; Villous; Visit; Vitamin A; Vitamin A Deficiency; Vulnerable Populations; Woman; Work; alpha 1-Antitrypsin; career development; cohort; dietary; egg; experience; gut health; immune activation; immune function; immunoregulation; improved; innovation; intestinal barrier; intestinal epithelium; intestinal fatty acid binding protein; low and middle-income countries; microbial; modifiable risk; mortality; neglected tropical diseases; nutrition; pathogen; phase II trial; response; response biomarker

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.

项目摘要/摘要 该提案的总体目标是促进我们对维生素A缺乏症的作用的理解 血吸虫病和环保肠功能障碍（EED）的发病机理，并促进职业生涯 候选人的发展。了解维生素A缺乏在发病机理中的机械作用 肠道血吸虫病将为基于营养的干预措施提供机会减少感染有关的机会 发病率。在低收入和中等收入国家（LMIC）中，营养不良的重叠和 感染对婴儿和儿童有重大健康后果，包括线性增长受损和 发育迟缓。发育迟缓会影响居住在LMIC的儿童中的三分之一，并可能对教育产生终身影响 妇女的成果，经济生产力和出生结果。维生素A缺乏，肠道 血吸虫病和EED都为童年时期的营养不足和发育迟缓做出了贡献，并可能共享 通过肠道屏障功能障碍的机制，随之而来的是全身免疫反应的激活。 动物模型和人类的研究为这些伤害在受损中的作用提供了科学前提 线性增长。最近开发的注射调整策略允许确定维生素A 感染或注射个体的状态，但尚未研究调整后的维生素A 在人类血吸虫病或EED的背景下的状态。拟议的研究将利用福祉 来自正在进行的NIH资助的随机，受控的II期试验的样品和临床数据（R01） praziquantel（PZQ）治疗的HD095562 n = 300岁以下的儿童曼森（Scistosoma） 乌干达阿尔伯特湖地区的感染。父母试验假设与 血吸虫病（营养不良，炎症贫血和线性生长阻滞）部分由EED驱动 因此，吸收不良和全身免疫激活。拟议的研究将增加 在父审判中收集的样品中维生素A的测量，以检查机制 炎症调整后的维生素A缺乏症有助于EED和血吸虫病相关的发病率。这 拟议的研究将1）检查调整后的维生素A状态与曼氏链球菌之间的关系 在基线访问时收集的感染强度和免疫反应标记和2）评估 维生素A状态与基线和纵向的EED生物标志物之间的关系，以响应于 PZQ治疗。这项工作将解决有关维生素A状态在 在曼氏链球菌感染的背景下，EED的病理生理及其对治疗效率的影响。此外， 拟议的培训计划将推进候选人的职业发展，a）建筑主题 血吸虫病和EED的免疫发病发生方面的物质专业知识，b）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的实施， c）扩大方法论能力以包括纵向数据分析。