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.

项目总结/摘要 本提案的总体目标是促进我们对维生素A缺乏症在以下方面作用的理解： 血吸虫病的发病机制和环境肠道功能障碍（EED）， 候选人的发展。了解维生素A缺乏症在发病机制中的作用 肠道血吸虫病的流行将为基于营养的干预措施提供机会， 发病率在低收入和中等收入国家， 感染对婴儿和儿童健康有重大影响，包括线性生长受损， 发育不良发育迟缓影响到生活在中低收入国家的三分之一儿童，并可能对教育造成终身影响。 结果，经济生产力和妇女的生育结果。维生素A缺乏症，肠 血吸虫病和EED都导致儿童营养不良和发育迟缓， 通过肠屏障功能障碍与伴随的全身免疫应答激活的机制。 来自动物模型和人类的研究为这些损伤在受损神经元中的作用提供了科学前提。 线性增长最近开发的炎症调节策略允许测定维生素A 感染或炎症个体的维生素A水平，但没有研究检查调整后的维生素A水平。 在人类血吸虫病或EED的背景下的状态。这项研究将利用良好的- 来自NIH资助的一项正在进行的随机对照II期试验（R 01）的特征样本和临床数据 HD 095562）吡喹酮（PZQ）治疗N = 300例4岁以下曼氏血吸虫病儿童的临床研究 在乌干达的阿尔伯特湖地区感染。母体试验假设， 血吸虫病（营养不良、炎症性贫血和线性生长发育迟缓）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 测量从母试验中收集的样本中的维生素A，以检查其机制 炎症调节的维生素A缺乏导致EED和与侏儒症相关的发病率。的 拟议的研究将1）检查调整后的维生素A状态和S之间的关系。曼氏 在基线访视时收集的感染强度和免疫应答标志物，以及2）评估 维生素A状态和EED生物标志物之间的关系，无论是在基线还是纵向， PZQ治疗。这项工作将解决关于维生素A状态在糖尿病中的作用的创新假设。 EED的病理生理学在S.曼森感染及其对治疗效果的影响。此夕h 拟议的培训计划将促进候选人在a）建筑学科方面的职业发展 血吸虫病和EED免疫发病机制方面的专业知识，B）获得以下方面的研究经验： 在申办者的监督下在弱势人群中实施随机对照试验， 以及c）扩大方法能力，以包括纵向数据分析。