Impact of HIV infection on early responses to TB exposure

HIV 感染对结核病暴露早期反应的影响

• 批准号: 10117169
• 负责人: Sara Auld
• 金额: $ 19.15万
• 依托单位: EMORY UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2018
• 资助国家: 美国
• 起止时间: 2018-04-01 至 2024-03-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10117169
• 关键词: Address; Adult; Affect; Alveolar Macrophages; Anti-Inflammatory Agents; Apoptosis; Area; Award; Biological Assay; Biometry; Bronchoscopy; CD4 Lymphocyte Count; Cause of Death; Cells; Characteristics; Clinical; Clinical Investigator; Clinical Research; Communicable Diseases; Communities; Data; Defect; Development Plans; Disease; Eligibility Determination; Epidemic; Epidemiology; Exposure to; Functional disorder; Funding; Future; Goals; HIV; HIV Infections; HIV Seronegativity; HIV Seropositivity; HIV/TB; Household; Human; Immune System Diseases; Immune response; Immunologic Deficiency Syndromes; Immunologics; Immunologist; Immunology; Impairment; Incidence; Individual; Inflammatory; Inflammatory Response; Infrastructure; Interferon Type II; Interferons; Interleukin-10; Interleukin-2; International; Intervention; K-Series Research Career Programs; Kenya; Knowledge; Lead; Lung; Mediating; Mentored Patient-Oriented Research Career Development Award; Mentors; Mentorship; Methodology; NIH Office of AIDS Research; Natural Immunity; Outcome; Participant; Patients; Phenotype; Positioning Attribute; Prospective Studies; Prospective cohort; Public Health; Pulmonary Tuberculosis; Pulmonology; Regression Analysis; Research; Research Project Grants; Resources; Risk; Scientist; Site; T cell response; T-Lymphocyte; T-Lymphocyte Subsets; TNF gene; Techniques; Testing; Time; Training; Translating; Tuberculin Test; Tuberculosis; United States National Institutes of Health; Universities; Work; adaptive immunity; antiretroviral therapy; career development; clinical epidemiology; co-infection; cohort; collaborative environment; comorbidity; cytokine; design; experience; improved; indexing; infection risk; insight; lung injury; macrophage; mortality; multidisciplinary; pathogen; prevent; programs; prospective; public health research; recruit; research and development; response; screening; secondary analysis; statistics; translational study

Project Summary/Abstract This K23 proposal outlines a 5-year career development plan and research strategy that will enable Sara Auld, MD, MSc, to build on her background in global TB/HIV research and clinical epidemiology and gain critical training in prospective clinical research, advanced biostatistics, and T cell and pulmonary immunology. To achieve independence as a clinical investigator with a unique niche as a practicing pulmonologist and an expertise in the epidemiologic and immunologic consequences of TB-HIV coinfection, Dr. Auld requires further training in: 1) recruitment and management of prospective cohorts, specifically the conduct of clinical studies in resource-limited international settings; 2) advanced statistics, including multilevel regression analyses capable of adjusting for household and individual-level characteristics; and 3) translational immunology, with a focus on T cell and pulmonary immune responses to TB exposure. Dr. Auld has outlined a plan of didactic coursework and assembled a multidisciplinary mentorship team. Her primary mentor is Dr. Neel Gandhi, an expert in clinical epidemiology and the conduct of global TB/HIV research. Her co-mentors are Dr. Cheryl Day, a translational immunologist with an expertise in human T cell immunology in TB/HIV coinfection, Dr. Lance Waller, a biomedical statistician with decades of experience in public health research, and Dr. David Guidot, a renowned pulmonary clinician scientist with a robust research program exploring HIV-mediated lung injury and alveolar macrophage dysfunction. With the support of this K23 award, Dr. Auld will address the question of how HIV infection impacts the response to TB exposure. She will first leverage data generated by the screening protocols of the Emory/NYU TB Research Unit (TBRU; U19 AI111211) to determine how HIV affects the acquisition of TB infection among household contacts of TB patients in Kisumu, Kenya (Aim 1). Next, levels of pro-inflammatory, anti- inflammatory, and regulatory cytokines generated by TB-specific T cells, and the phenotype of those cells will be compared for household contacts with and without HIV (Aim 2). Finally, pulmonary immune responses to TB will be compared for people with and without HIV using research bronchoscopy in a separate cohort in Atlanta, GA (Aim 3). Knowledge gained from this study will translate into interventions to decrease the risk of TB infection and improve long-term outcomes for people with HIV. This research responds directly to the 2016 priority areas of the NIH Office of AIDS Research, which considers HIV-associated comorbidities such as TB to be a high priority topic. Emory University provides an exceptional intellectual and collaborative environment for this research. By building upon her prior research experience and training, the well-established TBRU research program in western Kenya, and methodologic training via coursework and expert mentorship, Dr. Auld is well positioned to accomplish the proposed aims and, ultimately, to apply for an R01 award focused on exploring the pulmonary response to TB exposure in a setting with a high burden of TB/HIV coinfection.

项目总结/摘要 这份K23提案概述了一个5年职业发展计划和研究战略， Auld，医学博士，理学硕士，以她在全球结核病/艾滋病研究和临床流行病学的背景为基础， 在前瞻性临床研究，先进的生物统计学，T细胞和肺免疫学的关键培训。 作为一名临床研究者，作为一名执业肺病学家和一名 在TB-HIV合并感染的流行病学和免疫学后果方面的专业知识，Auld博士需要进一步研究 培训：1）招募和管理前瞻性队列，特别是在以下方面进行临床研究： 资源有限的国际环境; 2）先进的统计，包括能够进行多层次回归分析 调整家庭和个人水平的特点;和3）翻译免疫学，重点是 T细胞和肺对结核暴露的免疫反应。奥尔德博士概述了一个教学课程计划 组建了一个多学科的导师团队。她的主要导师是尼尔·甘地博士， 临床流行病学和开展全球结核病/艾滋病毒研究。她的共同导师是谢丽尔·戴博士， Lance博士是一位翻译免疫学家，在结核病/艾滋病病毒合并感染的人类T细胞免疫学方面具有专长， 沃勒博士是一位生物医学统计学家，在公共卫生研究方面有数十年的经验，大卫吉多特博士是一位 著名的肺部临床医生科学家，拥有强大的研究计划，探索艾滋病毒介导的肺损伤， 肺泡巨噬细胞功能障碍 在K23奖的支持下，Auld博士将解决艾滋病毒感染如何影响 对结核病的反应。她将首先利用埃默里/纽约大学筛选方案产生的数据 结核病研究股（TBRU; U19 AI 111211），以确定艾滋病毒如何影响结核病感染的获得， 肯尼亚基苏穆结核病患者的家庭接触者（目标1）。接下来，促炎，抗- 炎性和调节性细胞因子，这些细胞的表型将 对有和无艾滋病毒的家庭接触者进行比较（目标2）。最后，肺免疫反应， 将在2009年的一个单独队列中，使用研究性支气管镜检查对携带和不携带艾滋病毒的结核病患者进行比较。 亚特兰大，佐治亚州（目标3）。从这项研究中获得的知识将转化为干预措施，以降低 结核病感染和改善艾滋病毒感染者的长期结果。这项研究直接回应了2016年 美国国立卫生研究院艾滋病研究办公室的优先领域，该办公室认为艾滋病毒相关的合并症，如结核病， 成为一个高度优先的话题。埃默里大学提供了一个特殊的智力和协作环境， 这项研究。通过建立在她以前的研究经验和培训，完善的TBRU研究 项目在肯尼亚西部，并通过课程和专家指导的方法培训，奥尔德博士是很好的 能够实现所提出的目标，并最终申请R 01奖，重点是探索 在结核病/艾滋病病毒合并感染负担高的环境中，肺对结核病暴露的反应。