Mechanisms & risk factors of chronic lung disease in HIV+ adolescents in Nairobi

项目摘要/摘要 候选人：阿提亚博士的长期目标是在全球范围内改善肺部健康，进行临床研究和试验 在慢性肺部疾病方面，重点关注艾滋病毒和其他危险因素在影响 肺部疾病的病理生理和临床病程。本申请中提出的研究建立在她的基础上 以前的工作发现，慢性呼吸道症状和异常的患病率明显更高 在资源有限的情况下，HIV+青少年与成年人之间的肺活量测定。这个K23职业生涯 发展奖将为阿提亚博士提供必要的研究培训，以支持她成为一名 在肺部疾病、艾滋病毒和全球健康的交叉点上的独立研究员。通过这个项目， 阿提亚博士将实现她的直接目标，即获得以下学习中概述的专业知识 目标：1)关于测量和分析青少年肺生长的培训；2)设计和分析 实施纵向研究；3)质量控制和监测前瞻性研究；4)推进 分析复杂数据的生物统计学方法；以及5)负责任地实施研究活动 国际背景。这些目标将通过一个结构化的职业发展计划来实现 结合正式课程，由具有肺病集体专业知识的咨询委员会进行指导 疾病和肺生长、艾滋病毒、儿科、流行病学、生物统计学和临床中生物有机磷农药的使用 研究，以及获得实际研究经验的受保护时间。 环境：华盛顿大学(UW)丰富的学术环境是博士的理想去处。 阿提亚的持续研究训练。威斯康星大学是一家杰出的生物医学研究机构，拥有强大的 致力于促进有前途的研究人员的学术生涯。威斯康星州大学肺与外科分部 重症监护医学因其临床研究培训轨迹而得到广泛认可，并提供 支持发展与其他调查人员合作所需技能的环境 取得学业上的成功。除了该司内提供的资源和支助外，阿提亚博士还将 还可以完全访问华盛顿大学全球卫生教学、研究和专家部门的资源 教育(TREE)计划(由她的共同导师指导)，该计划提供行政、临床、实验室 和数据库管理基础设施，支持威斯康星大学附属科普特希望医院的临床研究 肯尼亚内罗毕传染病中心。阿提亚博士将接受有针对性的培训和指导 获取和分析青少年的肺活量作为肺生长和发育的衡量标准 华盛顿大学儿科和华盛顿大学领导的多部位囊性纤维化临床试验网络的资源， 囊性纤维化治疗发展网络。阿提亚博士还将获得临床研究和 通过威斯康星大学公共卫生学院和转化健康科学研究所提供生物统计学支持 项目(威斯康星大学临床与转化科学奖项目)。 研究：阿提亚博士将检查患病率、亚型、风险因素和发病机制的差异 慢性肺部疾病，通过基线和两年多的支气管扩张剂前后重复肺活量测定来检测 来自希望中心的150名HIV+青少年与150名HIV对照组相比，年龄和性别成组匹配。 在HIV+青少年中，慢性肺部疾病将通过基线胸部CT扫描进一步表现出来。她 将在基线时确定艾滋病毒感染对慢性肺部疾病表现的作用以及 肺功能随时间的变化，考虑到与其他危险因素的复杂相互作用，包括 营养不良和室内生物燃料燃烧。她还将评估艾滋病毒疾病的严重性和生物标记物 慢性免疫激活和炎症与慢性肺部疾病患病率的增加有关 随着时间的推移，疾病和肺功能发育减退。本申请中提出的研究具有创新性。 因为它标志着1)直接表征慢性阻塞性肺疾病的流行病学和病理生理学的第一项研究 在资源有限的情况下，HIV+与HIV青少年肺部疾病的比较，2)确定危险因素 与HIV+相比，通过重复肺活量测定法评估，随着时间的推移，HIV+与HIV+的肺功能变化有关 以及3)确定慢性免疫激活、炎症和艾滋病毒的血清标志物 严重程度与慢性肺部疾病有关，提供了潜在的机械性见解。这方面的发现 研究将为慢性肺的亚型和病理生理机制提供新的见解 在资源有限的环境中艾滋病毒+青少年的疾病发展和进展，揭示了风险 预防和治疗干预措施可以针对的因素和机制，以缓解 慢性肺部疾病的负担。

PROJECT SUMMARY/ABSTRACT Candidate: Dr. Attia's long-term goal is to improve lung health globally, conducting clinical research and trials in chronic lung diseases, with a focus on the role of HIV and other risk factors in influencing the pathophysiology and clinical course of lung disease. The research proposed in this application builds on her previous work, which found a significantly greater prevalence of chronic respiratory symptoms and abnormal spirometry among HIV+ adolescents compared to adults in a resource-limited setting. This K23 Career Development Award will provide Dr. Attia with essential research training to support her goal of becoming an independent investigator at the intersection of pulmonary disease, HIV and global health. Through this project, Dr. Attia will accomplish her immediate goals of attaining the expertise outlined in the following learning objectives: 1) training in measurement and analysis of lung growth in adolescents; 2) design and implementation of longitudinal studies; 3) quality control and monitoring of prospective studies; 4) advanced biostatistical methods to analyze complex data; and 5) responsible implementation of research activities in an international setting. These objectives will be achieved through a structured career development plan that incorporates formal coursework, mentoring by an advisory committee with collective expertise in pulmonary disease and lung growth, HIV, pediatrics, epidemiology, biostatistics and the use of biospecimens in clinical research, as well as protected time to gain practical research experience. Environment: The rich academic environment at the University of Washington (UW) is an ideal place for Dr. Attia's continued research training. UW is an outstanding biomedical research institution with a strong commitment to promoting the academic careers of promising investigators. The UW Division of Pulmonary and Critical Care Medicine is widely recognized for its Clinical Research Training Track and offers an intellectual environment that supports development of the skills necessary to collaborate with other investigators and achieve academic success. In addition to the resources and support provided within the Division, Dr. Attia will also have full access to the resources of the UW Department of Global Health Teaching, Research and Expert Education (TREE) program (directed by her co-mentor), which provides the administrative, clinical, laboratory and database management infrastructure that supports clinical research at the UW-affiliated Coptic Hope Center for Infectious Diseases in Nairobi, Kenya. Dr. Attia will receive directed training and mentoring in obtaining and analyzing spirometry in adolescents as a measure of lung growth and development through the resources of the UW Department of Pediatrics and the UW-led multi-site cystic fibrosis clinical trials network, Cystic Fibrosis Therapeutics Development Network. Dr. Attia will also have access to clinical research and biostatistical support through the UW School of Public Health and the Institute of Translational Health Sciences program (the Clinical and Translational Science Award program at UW). Research: Dr. Attia will examine differences in the prevalence, subtypes, risk factors and mechanisms of chronic lung disease, detected by baseline and repeat pre- and post-bronchodilator spirometry over 2 years in 150 HIV+ adolescents from the Hope Center compared to 150 HIV- controls, block-matched on age and sex. Among HIV+ adolescents, chronic lung disease will be further characterized with baseline chest CT scans. She will determine the role of HIV infection on the manifestations of chronic lung disease at baseline and the change in lung function over time, considering the complex interplay with other risk factors including malnutrition and indoor biofuel burning. She will also evaluate whether severity of HIV disease, and biomarkers of chronic immune activation and inflammation are associated with an increased prevalence of chronic lung disease and diminished lung function growth over time. The research proposed in this application is innovative because it signifies the first study to 1) directly characterize the epidemiology and pathophysiology of chronic lung disease in HIV+ compared to HIV- adolescents in a resource-limited setting, 2) ascertain risk factors associated with change in lung function over time, assessed by repeated spirometry, in HIV+ compared to HIV- adolescents, and 3) determine whether serum markers of chronic immune activation, inflammation and HIV severity are associated with chronic lung disease, providing potential mechanistic insights. Findings of this research will provide novel insights into the subtypes and pathophysiologic mechanisms of chronic lung disease development and progression in HIV+ adolescents in resource-limited settings, shedding light on risk factors and mechanisms that can be targeted by preventative and therapeutic interventions to mitigate the burden of chronic lung disease.