Clinical and biologic risk factors for post-tuberculosis lung disease (PTLD) in people with and without HIV

项目摘要/摘要： 曾傑瑞，医学博士，公共卫生硕士，计划作为一名内科科学家发展独立的研究生涯， 重点是提高撒哈拉以南非洲对肺部疾病的认识和结果。这个 拟议的职业发展奖的目标是提供必要的研究培训 促进Zifodya博士向独立研究过渡的方法。杜兰大学提供的导师制 华盛顿大学(UW)和肯尼亚医学研究所(KEMRI) 都是杰出的。他将在Jay Kolls博士(TU)David Horne的指导下继续工作 (UW)和克里斯蒂娜·克罗瑟斯(UW)。他的多学科研究团队的合作者和导师 跨越肯尼亚结核病(TB)研究的学科(Videlis Nduba博士，KEMRI)，全球艾滋病毒 流行病学(TU帕特里夏·基辛格博士)、结核病免疫学(TU托马斯·霍恩博士)、高级统计学 (苏迪什·斯里瓦斯塔瓦博士)和生物信息学(王玉平博士，TU)。以补充来自以下方面的支持 他的导师，Zifodya博士将在国际知名的 清华大学公共卫生与热带医学学院和清华大学生物医学研究生院。 结核病是主要的机会性感染，也是全球发病率和死亡率的主要原因。 艾滋病毒携带者。即使对结核病进行了适当的治疗，多达一半的肺结核患者 发展为结核病后肺部疾病(PTLD)，定义为以下慢性呼吸异常 肺结核病。PTLD的潜在机制尚不清楚。迫切需要定义 PTLD的长期轨迹，并确定宿主临床、免疫学和遗传风险因素。这个 这项建议的总体目标是确定(I)临床宿主因素和(Ii)宿主炎症和 预测PTLD的免疫学因素。在初步研究中，我们已经表明PTLD很常见， 与炎症标志物升高有关。我们假设炎症性和非传染性疾病 肺结核后免疫激活途径预测PTLD并被HIV扭曲(依赖于 免疫妥协程度)。我们将在肯尼亚成年人的纵向队列中测试这些假设 与结核病相关的两个具体目标：1：确定与肺功能相关的宿主特征 对感染和未感染艾滋病毒的肯尼亚成年人进行了两年多的随访，结果显示下降和PTLD。2：确定是否 活化的PBMCs的转录反应可以预测肺功能受损和PTLD。 该奖项将在低成本的纵向研究中提供必要的研究培训 生物标志物的资源设定、测量和分析，以及对 免疫学数据。在这个K23的支持下，Zifodya博士拥有的研究和培训计划 设计将帮助他实现成为一名独立调查员的长期目标。

PROJECT SUMMARY/ABSTRACT: Jerry Zifodya, MD, MPH plans to develop an independent research career as a physician-scientist, focused on improving the understanding and outcomes of lung disease in sub-Saharan Africa. The objective of the proposed career development award is to provide necessary training in research methods to facilitate Dr. Zifodya’s transition to independent research. The mentorship available at Tulane University (TU), the University of Washington (UW), and the Kenyan Medical Research Institute (KEMRI) are outstanding. He will continue his work under the mentorship of Drs. Jay Kolls (TU), David Horne (UW), and Kristina Crothers (UW). Collaborators and mentors on his multi-disciplinary research team span the disciplines of tuberculosis (TB) research in Kenya (Dr. Videlis Nduba, KEMRI), global HIV epidemiology (Dr. Patricia Kissinger, TU), TB immunology (Dr. Thomas Hawn, TU), advanced statistics (Dr. Sudesh Srivastav, TU) and bioinformatics (Dr. Yu-Ping Wang, TU). To complement the support from his mentors, Dr. Zifodya will augment his MPH with advanced coursework at the internationally renowned TU School of Public Health & Tropical Medicine and TU Biomedical Sciences Graduate Program. TB is the leading opportunistic infection and primary cause of morbidity and mortality worldwide for people with HIV. Even with adequate treatment of TB, up to half of all persons with pulmonary TB develop post-TB lung disease (PTLD), which is defined by chronic respiratory abnormality after pulmonary TB. The underlying mechanisms of PTLD are unclear. There is a critical need to define the long-term trajectory of PTLD and identify host clinical, immunological, and genetic risk factors. The overall objectives for this proposal are to identify (i) clinical host factors and (ii) host inflammatory and immunological factors that predict PTLD. In preliminary studies we have shown PTLD to be common and associated with elevated inflammatory markers. We hypothesize that upregulation of inflammatory and immune activation pathways after pulmonary TB predicts PTLD and is skewed by HIV (dependent on degree of immunocompromise). We will test these hypotheses in a longitudinal cohort of Kenyan adults with TB with the two specific aims: 1: Determine host characteristics associated with pulmonary function decline and PTLD over 2 years of follow-up in Kenyan adults with and without HIV. 2: Determine whether transcriptomic responses in activated PBMCs can predict impaired pulmonary function and PTLD. This award will provide essential research training in the conduct of longitudinal studies in a low resource setting, measurement and analysis of biomarkers, and interpretation and integration of immunologic data. With the support of this K23, the research and training plan that Dr. Zifodya has devised will assist him in achieving his long-term goal of becoming an independent investigator.