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.

项目摘要/摘要 这项K23提案概述了一项为期5年的职业发展计划和研究策略，该计划将使Sara能够 Auld，MD，MSC，以她在全球结核/艾滋病毒研究和临床流行病学领域的背景为基础 前瞻性临床研究，晚期生物统计学以及T细胞和肺免疫学的重要培训。 作为作为临床研究者独立的独立性 TB-HIV共感染的流行病学和免疫学后果的专业知识，Auld博士需要进一步 培训：1）招募和管理前瞻性队列，特别是在 资源有限的国际环境； 2）高级统计数据，包括能够多级回归分析 调整家庭和个人水平特征； 3）转化免疫学，重点 T细胞和对结核病暴露的肺免疫反应。 Auld博士概述了教学课程的计划 并组建了一个多学科指导团队。她的主要导师是Neel Gandhi博士，专家 临床流行病学和全球结核病/艾滋病毒研究的行为。她的联合官员是谢丽尔·戴（Cheryl Day） TB/HIV共感染的人类T细胞免疫学专业知识的转化免疫学家，Lance博士 沃勒（Waller）是一位生物医学统计学家，拥有数十年的公共卫生研究经验，戴维·吉多特（David Guidot）博士 著名的肺临床医师科学家，由一项强大的研究计划，探讨HIV介导的肺损伤和 肺泡巨噬细胞功能障碍。 在该K23奖的支持下，Auld博士将解决HIV感染如何影响的问题 对结核病暴露的反应。她将首先利用Emory/NYU的筛选协议产生的数据 结核病研究单位（TBR; U19 AI111211）确定HIV如何影响收购结核病感染 肯尼亚Kisumu的结核病患者的家庭接触（AIM 1）。接下来，促炎性，抗炎水平 TB特异性T细胞产生的炎症和调节细胞因子，这些细胞的表型将 比较有或没有艾滋病毒的家庭接触（AIM 2）。最后，肺免疫反应 使用研究支气管镜检查在一个单独的队列中使用研究支气管镜检查的患者将与TB进行比较 佐治亚州亚特兰大（AIM 3）。从这项研究中获得的知识将转化为干预措施，以降低 结核病感染并改善艾滋病毒患者的长期结局。这项研究直接回应2016年 NIH AIDS研究办公室的优先领域，该领域认为与TB等艾滋病毒相关的合并症 成为高优先级主题。埃默里大学（Emory University）为智力和协作环境提供 这项研究。通过基于她先前的研究经验和培训，TBRU研究 肯尼亚西部的计划以及通过课程和专家指导的方法学培训，Auld博士很好 定位实现拟议的目标，并最终申请重点探索的R01奖项 在TB/HIV共感染负担很大的情况下，对结核病暴露的肺反应。