HIV Infection, Placental Inflammation, and Early Childhood Outcomes in HIV-exposed, Uninfected Infants in Uganda

乌干达暴露于 HIV 的未感染婴儿的 HIV 感染、胎盘炎症和早期儿童结局

基本信息

批准号：
10543082
负责人：
Lisa M Bebell
金额：
$ 27.19万
依托单位：
MASSACHUSETTS GENERAL HOSPITAL
依托单位国家：
美国
项目类别：
财政年份：
2019
资助国家：
美国
起止时间：
2019-01-14 至 2023-12-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10543082
关键词：
Africa Africa South of the Sahara Biology Biometry Birth CD4 Lymphocyte Count Career Choice Caring Cessation of life Child Child Health Chronic Classification Clinical Clinical Investigator Clinical Trials Design Cytomegalovirus Data Early treatment Enrollment Ensure Functional disorder Funding Goals Growth HIV HIV Infections HIV-exposed uninfected infant Haemophilus influenzae type b Health Histologic Histology Histopathology Hospitalization Immune Immunology Incidence Infant Infant Health Infection Inflammation Inflammatory Institution Intervention Late pregnancy Learning Life Link Malaria Manuscripts Maternal Health Maternal and Child Health Maternal-Fetal Exchange Measures Mediating Mediation Mediator Mentors Mentorship Methods Morbidity - disease rate Mother-to-child HIV transmission Mothers Mycoplasma Outcome Participant Pathologist Pathology Perinatal Pharmaceutical Preparations Pilot Projects Placenta Positioning Attribute Pregnant Women Prevalence Prevention program Prospective cohort Publications Publishing Quasi-experiment Regimen Reporting Research Research Personnel Risk Role Site Source Specimen Streptococcus pneumoniae Techniques Training Uganda United States National Institutes of Health Ureaplasma Viremia Woman Work adverse outcome antibody transfer antiretroviral therapy career co-infection cohort comparison group early childhood effective intervention experience global health immune activation improved improved outcome infant morbidity/mortality infant outcome innovation intraamniotic infection mortality multidisciplinary pathogen placental infection respiratory pathogen skill acquisition success systemic inflammatory response theories vaccination strategy

项目摘要

PROJECT SUMMARY Background: Successful mother-to-child HIV transmission prevention programs have decreased the global incidence of congenital HIV. Yet, >1 million HIV-exposed, uninfected (HEU) children are born annually in sub- Saharan Africa and have poorer early-life outcomes than HIV-unexposed children. The pathophysiology of these poor outcomes is poorly understood, yet critical to developing effective interventions to improve outcomes for these children. I hypothesize that placental inflammation may contribute to adverse HEU child health outcomes by decreasing quality and quantity of transplacental antibody transfer and disrupting normal pathogen barrier functions. Candidate: My overarching career goal is to become an independent, NIH-funded clinical investigator with expertise in the contribution of maternal infections, the placenta, and inflammation to health outcomes of HIV-exposed children. My clinical work caring for women living with HIV (WLWH) and their infants and conducting research investigating maternal-child health outcomes has inspired this career path. I am well-prepared to undertake the scientific and training aims proposed here, having successfully published eight first-author manuscripts and completed a 50-placenta histology pilot study in Uganda in 2016. Mentoring: Dr. Ingrid Bassett (Primary Mentor) is an NIH-funded investigator who has successfully mentored 4 NIH K23 awardees. Dr. Drucilla Roberts (Co-mentor, Pathology) has been a perinatal pathologist for nearly 30 years and worked in Africa for over a decade. Drs. Mark Siedner (Global Health), Galit Alter (Immunology), Joseph Ngonzi (Uganda Site), Roger Shapiro (HEU Outcomes), Bethany Hedt-Gauthier (Biostatistics), and Elias Kumbakumba (Infant Outcomes) will provide additional focused mentorship to ensure my success. Research: I will enroll a prospective cohort of 300 WLWH on ART in late pregnancy and a comparison group of 150 HIV-uninfected pregnant women in Uganda and collect their placentas at birth. I will compare the prevalence of inflammatory placental abnormalities by maternal HIV serostatus and determine the correlates of inflammatory placental abnormalities in WLWH. Potential correlates include maternal factors (CD4 count, ART regimen, CMV viremia) and placental factors (detectable placental HIV and placental infections). I will measure transplacental respiratory pathogen antibody transfer as surrogate immune measures of placental function, and follow infants born to enrolled women for 12 months to determine the association of inflammatory placental abnormalities with HEU infant morbidity and mortality. Training: To achieve my aims and gain research independence, I require additional training in: 1) placental histopathology, biology, and immunology 2) causal inference theory, with a focus on mediation analysis, and 3) clinical trial design to conduct a larger R01-funded study of placental inflammation in Uganda. Based on my previous research experience and success, support from an exceptional mentoring team, strong institutional commitment, and an innovative research plan, I am well-positioned to become an independent clinical investigator focused on maternal-child health in WLWH.

项目概要背景：成功的母婴艾滋病毒传播预防计划减少了全球艾滋病毒传播先天性艾滋病毒的发病率。然而，每年有超过 100 万暴露于 HIV 的未感染 (HEU) 儿童出生在亚撒哈拉非洲地区的儿童的早期生活结果比未接触艾滋病毒的儿童更差。病理生理学人们对这些不良结果知之甚少，但对于制定有效的干预措施以改善结果至关重要这些孩子的结果。我推测胎盘炎症可能会导致 HEU 儿童出现不良反应通过降低经胎盘抗体转移的质量和数量并破坏正常的健康结果病原体屏障功能。候选人：我的总体职业目标是成为一名独立的、由 NIH 资助的人临床研究者，在孕产妇感染、胎盘和炎症影响方面具有专业知识感染艾滋病毒的儿童的健康结果。我的临床工作是照顾艾滋病毒感染者 (WLWH) 及其她们婴儿和开展母婴健康结果的研究启发了这一职业道路。我我已做好充分准备来实现此处提出的科学和培训目标，并已成功发表八篇第一作者手稿，并于 2016 年在乌干达完成了 50 个胎盘组织学试点研究。指导：Ingrid Bassett 博士（主要导师）是一位 NIH 资助的研究员，已成功指导 4 名 NIH K23 获奖者。 Drucilla Roberts 博士（病理学联合导师）担任围产期病理学家近 30 年并在非洲工作了十多年。博士。 Mark Siedner（全球健康）、Galit Alter（免疫学）、 Joseph Ngonzi（乌干达站点）、Roger Shapiro（HEU 结果）、Bethany Hedt-Gauthier（生物统计学）和 Elias Kumbakumba（婴儿成果）将提供额外的重点指导，以确保我的成功。研究：我将招募 300 名妊娠晚期接受 ART 的 WLWH 前瞻性队列和对照组乌干达 150 名未感染艾滋病毒的孕妇并在她们出生时收集胎盘。我将比较通过母亲 HIV 血清状态确定炎症性胎盘异常的患病率，并确定以下因素的相关性： WLWH 中的炎症性胎盘异常。潜在相关因素包括母体因素（CD4 计数、ART 治疗方案、CMV 病毒血症）和胎盘因素（可检测的胎盘 HIV 和胎盘感染）。我会测量经胎盘呼吸道病原体抗体转移作为胎盘功能的替代免疫措施，并对登记妇女所生的婴儿进行 12 个月的跟踪以确定炎症性胎盘的关联 HEU 婴儿发病率和死亡率异常。培训：实现我的目标并获得研究成果为了独立，我需要以下方面的额外培训：1) 胎盘组织病理学、生物学和免疫学 2) 因果关系推理理论，重点是中介分析，以及 3) 进行更大规模的 R01 资助的临床试验设计乌干达胎盘炎症研究。根据我之前的研究经验和成功，支持凭借出色的指导团队、强有力的机构承诺和创新的研究计划，我完全有能力成为 WLWH 中专注于母婴健康的独立临床研究者。