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

项目总结/摘要 候选人：Attia博士的长期目标是改善全球肺部健康，进行临床研究和试验 在慢性肺部疾病中，重点是艾滋病毒和其他危险因素在影响 肺疾病的病理生理学和临床过程。这项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 在资源有限的环境中，与成人相比，HIV阳性青少年的肺功能测定。K23职业生涯 发展奖将为Attia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的独立调查员。通过这个项目， 博士Attia将完成她的直接目标，即获得以下学习中概述的专业知识 目的：1）培训测量和分析青少年肺生长; 2）设计和 纵向研究的实施; 3）前瞻性研究的质量控制和监测; 4）先进的 生物统计学方法来分析复杂的数据;和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， 包括正式的课程，由咨询委员会指导，在肺 疾病和肺生长，艾滋病毒，儿科，流行病学，生物统计学和临床生物标本的使用 研究，以及保护时间，以获得实际的研究经验。 环境：华盛顿大学（UW）丰富的学术环境是博士的理想场所。 阿提亚的持续研究训练。UW是一个优秀的生物医学研究机构，具有强大的 致力于促进有前途的研究人员的学术生涯。UW肺科和 重症监护医学因其临床研究培训轨道而得到广泛认可，并提供了一个知识分子 支持发展与其他调查人员合作所需技能的环境， 取得学术成功。除了该司内部提供的资源和支持外，阿提亚博士还将 还可以充分利用全球卫生教学，研究和专家的UW部门的资源 教育（树）计划（由她的共同导师指导），提供行政，临床，实验室 和数据库管理基础设施，支持在华盛顿大学附属科普特希望临床研究 肯尼亚内罗毕的传染病中心。Attia博士将在以下方面接受指导性培训和指导： 获得和分析青少年的肺功能测定，作为肺生长和发育的测量方法， 华盛顿大学儿科系和华盛顿大学领导的多中心囊性纤维化临床试验网络的资源， 囊性纤维化治疗开发网络。Attia博士还将获得临床研究， 通过公共卫生和转化健康科学研究所的UW学院的生物统计支持 临床和转化科学奖（Clinical and Translational Science Award）。 研究：Attia博士将研究在患病率，亚型，风险因素和机制的差异， 慢性肺部疾病，通过基线和2年内重复使用支气管扩张剂前后肺功能测定检测， 来自希望中心的150名HIV+青少年与150名HIV-对照组进行了年龄和性别的区组匹配。 在HIV阳性青少年中，慢性肺部疾病将通过基线胸部CT扫描进一步表征。她 将确定HIV感染在基线时对慢性肺病表现的作用， 肺功能随时间的变化，考虑到与其他风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程度， 慢性免疫激活和炎症与慢性肺结核的患病率增加有关。 随着时间的推移，疾病和肺功能下降。本申请中提出的研究具有创新性 因为它标志着第一项研究：1）直接描述慢性疾病的流行病学和病理生理学特征， 在资源有限的环境中，与HIV-青少年相比，HIV+青少年的肺部疾病，2）确定风险因素 与HIV+与HIV-患者肺功能随时间的变化相关，通过重复肺量测定法评估 青少年，和3）确定是否慢性免疫激活，炎症和艾滋病毒的血清标志物 严重程度与慢性肺病相关，提供了潜在的机制见解。调查结果 这项研究将为慢性肺结核的亚型和病理生理机制提供新的见解。 资源有限环境中艾滋病毒阳性青少年的疾病发展和进展， 预防性和治疗性干预措施可以针对的因素和机制，以减轻 慢性肺病的负担。

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.