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.

项目概要/摘要 该提案的总体目标是增进我们对维生素 A 缺乏在 血吸虫病和环境肠道功能障碍（EED）的发病机制并促进职业发展 了解维生素 A 缺乏在发病机制中的机制作用。 肠道血吸虫病的发生将为基于营养的干预措施提供机会，以减少与感染相关的 在低收入和中等收入国家（LMIC），营养不良和发病率的重叠负担。 感染对婴儿和儿童具有严重的健康后果，包括线性生长受损和 发育迟缓影响了中低收入国家三分之一的儿童，并可能对教育造成终生影响。 维生素 A 缺乏、肠道的结果、经济生产力和出生结果。 血吸虫病和 EED 都会导致儿童营养不良和发育迟缓，并且可能有共同点 通过肠道屏障功能障碍并同时激活全身免疫反应的机制。 来自动物模型和人类的研究为这些损伤在受损患者中的作用提供了科学前提。 最近开发的炎症调节策略可用于测定维生素 A。 感染或炎症个体的状况，但没有研究检查调整后的维生素 A 拟议的研究将充分利用人类血吸虫病或 EED 的状况。 来自 NIH 资助的一项正在进行的随机对照 II 期试验（R01 HD095562) 吡喹酮 (PZQ) 治疗 N = 300 名 4 岁以下曼氏血吸虫儿童 乌干达阿尔伯特湖地区的感染父母试验英雄认为关键发病率与此相关。 血吸虫病（营养不良、炎症性贫血和线性生长发育迟缓）部分是由 EED 驱动的 拟议的研究将增加随之而来的吸收不良和全身免疫激活。 测量从母体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 缺乏会导致 EED 和血吸虫病相关的发病率。 拟议的研究将 1) 检查调整后的维生素 A 状态与曼氏沙门氏菌之间的关系 基线访视时收集的感染强度和免疫反应标记物，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 治疗将解决有关维生素 A 状态在疾病中的作用的创新假设。 曼氏沙门氏菌感染背景下 EED 的病理生理学及其对治疗效果的影响。 拟议的培训计划将促进候选人在以下方面的职业发展：a) 建设主题 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 在申办者的监督下对弱势群体实施随机对照试验， c) 扩展方法能力以包括纵向数据分析。