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

HIV感染者和未感染者结核后肺病（PTLD）的临床和生物学危险因素

• 批准号: 10488480
• 负责人: Jerry S. Zifodya
• 金额: $ 17.86万
• 依托单位: TULANE UNIVERSITY OF LOUISIANA
• 依托单位国家: 美国
• 财政年份: 2022
• 资助国家: 美国
• 起止时间: 2022-08-15 至 2027-07-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10488480
• 关键词: Acute-Phase Reaction; Adult; Africa South of the Sahara; Aftercare; Antigens; Award; Bioinformatics; Biological; Biological Assay; Biological Markers; C-reactive protein; CXCL9 gene; Characteristics; Chronic; Clinical; Cohort Studies; Complement; Consequences of HIV; Cross-Sectional Studies; DNA; Data; Development; Discipline; Enrollment; Enzyme-Linked Immunosorbent Assay; Epidemiology; Female; Genetic Transcription; Goals; HIV; HIV Infections; Hepatic; Immunocompromised Host; Immunogenetics; Immunologic Factors; Immunologic Markers; Immunologics; Immunology; Impairment; Individual; Infiltration; Inflammation; Inflammatory; Inflammatory Response; Integration Host Factors; Interdisciplinary Study; Interferon Type I; Interferons; International; Intervention; K-Series Research Career Programs; Kenya; Knowledge; Lead; Literature; Longitudinal Studies; Longitudinal cohort; Lung; Lung diseases; Measurement; Measures; Medical Research; Mentors; Mentorship; Modeling; Morbidity - disease rate; Neutrophil Collagenase; Newly Diagnosed; Opportunistic Infections; Outcome; Participant; Pathway interactions; Peripheral Blood Mononuclear Cell; Persons; Physicians; Plasma; Positioning Attribute; Predictive Factor; Prospective Studies; Proteins; Prothrombin; Public Health Schools; Publishing; Pulmonary Tuberculosis; Recording of previous events; Research; Research Institute; Research Methodology; Research Personnel; Research Training; Resource-limited setting; Risk; Risk Factors; Sampling; Science; Scientist; Signal Transduction; Spirometry; Symptoms; TNF gene; Techniques; Testing; Time; Training; Tropical Medicine; Tuberculosis; Universities; Up-Regulation; Washington; Work; base; career; chemokine; circulating biomarkers; cohort; follow-up; genetic risk factor; immune activation; improved; inflammatory marker; mortality; prevent; profiles in patients; programs; prospective; pulmonary function; pulmonary function decline; respiratory; response; responsible research conduct; statistics; transcriptome sequencing; transcriptomics; tuberculosis treatment

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.

项目概要/摘要： Jerry Zifodya，医学博士，公共卫生硕士计划作为一名医师科学家发展独立的研究生涯， 重点是提高撒哈拉以南非洲地区肺部疾病的认识和结果。这 拟议职业发展奖的目的是提供必要的研究培训 促进 Zifodya 博士过渡到独立研究的方法。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。他将在博士的指导下继续他的工作。杰·科尔斯 (TU)、大卫·霍恩 （威斯康星大学）和克里斯蒂娜·克罗瑟斯（威斯康星大学）。多学科研究团队的合作者和导师 涵盖肯尼亚结核病 (TB) 研究（Videlis Nduba 博士，KEMRI）、全球艾滋病毒研究 流行病学（Patricia Kissinger 博士，TU）、结核病免疫学（Thomas Hawn 博士，TU）、高级统计学 （Sudesh Srivastav 博士，TU）和生物信息学（Yu-Ping Wang 博士，TU）。为了补充来自 在他的导师 Zifodya 博士的指导下，Zifodya 博士将通过国际知名大学的高级课程来增强他的公共卫生硕士学位 TU 公共卫生与热带医学学院和 TU 生物医学科学研究生项目。 结核病是主要的机会性感染，也是全世界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，仍有多达一半的肺结核患者 发展为结核病后肺病 (PTLD)，其定义为结核病后的慢性呼吸系统异常 肺结核。 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、免疫和遗传危险因素。这 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 的免疫因素。在初步研究中，我们已经表明 PTLD 很常见并且 与炎症标志物升高有关。我们假设炎症和 肺结核后的免疫激活途径可预测 PTLD 并受到 HIV 的影响（取决于 免疫功能低下的程度）。我们将在肯尼亚成年人的纵向队列中测试这些假设 结核病有两个具体目标： 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 2 年随访，发现其病情下降和 PTLD。 2：判断是否 激活的 PBMC 中的转录组反应可以预测肺功能受损和 PTLD。 该奖项将为低水平纵向研究的开展提供必要的研究培训。 资源设置、生物标志物的测量和分析以及解释和整合 免疫学数据。在这台K23的支持下，Zifodya博士的研究和培训计划 设计的将帮助他实现成为一名独立调查员的长期目标。