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

项目总结/摘要： 杰里Zifodya，医学博士，公共卫生硕士计划发展一个独立的研究生涯作为一个医生，科学家， 重点是提高对撒哈拉以南非洲肺部疾病的认识和结果。的 拟议的职业发展奖的目的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。杜兰大学提供的指导 大学（TU）、华盛顿大学（UW）和肯尼亚医学研究所（KEMRI） 非常出色他将继续他的指导下博士杰伊·科尔斯（TU），大卫霍恩的工作 (UW)Kristina Crothers（UW）他的多学科研究团队的合作者和导师 跨越肯尼亚结核病研究的学科（Videlis Nduba博士，KEMRI），全球艾滋病毒 流行病学（帕特里夏·基辛格博士，TU）、结核病免疫学（托马斯·霍恩博士，TU）、高级统计学 (Dr. Sudesh Srivastav，TU）和生物信息学（Yu-Ping Wang博士，TU）。为了补充来自 他的导师，博士Zifodya将增加他的MPH与先进的课程，在国际知名的 TU公共卫生与热带医学学院和TU生物医学科学研究生课程。 结核病是世界范围内主要的机会性感染，也是发病率和死亡率的主要原因， 艾滋病毒感染者。即使结核病得到充分治疗， 发生结核病后肺部疾病（PTLD），其定义为 肺结核PTLD的潜在机制尚不清楚。目前迫切需要界定 PTLD的长期轨迹，并确定宿主的临床，免疫学和遗传风险因素。的 该提案的总体目标是确定（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，我们已经证明PTLD是常见的， 与炎症标志物升高有关我们推测，炎症和 肺结核后的免疫激活途径可预测PTLD， 免疫功能低下）。我们将在肯尼亚成年人的纵向队列中测试这些假设 有两个具体目标：1：确定与肺功能相关的宿主特征 下降和PTLD超过2年的后续行动，在肯尼亚成年人与非艾滋病毒。2：确定是否 活化PBMC中的转录组学应答可以预测肺功能受损和PTLD。 该奖项将提供必要的研究培训，在低水平的纵向研究进行 生物标志物的测量和分析，以及生物标志物的解释和整合。 免疫学数据。在K23的支持下，Zifodya博士的研究和培训计划 这将有助于他实现成为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.