The Role of Sex Steroid Hormones in CD4+ T Cell-mediated Immune Responses to Tuberculosis

摘要 这个福格蒂K43全球新兴领袖奖的目标是建立Djeneba Dabitao，药学博士，博士， 作为一个领先的，独立的调查员和未来的导师，在研究重点是性别差异的作用， 免疫反应、疾病易感性和感染性疾病的治疗结果，特别是 结核病（TB）。基于性别的生物学领域正在迅速扩大，有力的证据表明，男性 女性对微生物挑战、治疗和疫苗的反应也不同。我选择专注于 结核病，因为它仍然是西非马里等贫穷国家的主要公共卫生问题。事实上， 在该地区，男性结核病发病率平均比女性高2至3倍。然而，尽管令人信服， 数据表明，男性是发展活动性肺结核（TB+）的独立危险因素， 了解男性患病率高于女性的潜在机制。我假设 性激素影响CD 4 + T细胞介导的对结核病的免疫反应。为了验证这个假设，我将 评估男性和女性结核病阳性患者之间的免疫反应差异（目标1），并比较 性类固醇激素对男性和女性TB+离体免疫反应的影响（目的2）。研究 该计划与科学、技术和环境大学之间现有的联合研究活动保持一致， 马里巴马科科技大学、西北大学和约翰霍普金斯大学 (JHU)在美国，其中包括非洲分枝杆菌感染期间宿主-病原体相互作用的R 01 （R 01 AI 110386; PI：Diallo）和Fogarty国际中心关于艾滋病毒和分枝杆菌疾病的培训补助金 （D43 TW 010350，共同PI：Diallo和Murphy）。我还将利用卓越的BSL 3和ImmunoCore 设施和资源，可在大学临床研究中心（UCRC），由NIAID资助，根据 Clifford Lane，MD和Seydou Doumbia，MD PhD的领导。对于这个K43，我将追求说教， 结构化教程和体验式实验室培训，以确保获得四个基本领域的专业知识 对我来说，成为疾病易感性、治疗学和潜在的性别差异领域的领导者， 疫苗开发，即：（1）免疫内分泌学，（2）分枝杆菌学，（3）流行病学， 生物统计学和研究设计，以及（4）赠款和手稿准备和有效 科学介绍。我有一个来自马里和美国的优秀的多学科专家指导团队， 包括联合小学导师，Souleymane Diallo，MD（USTB）和Robert Murphy，MD（NU）; William Bishai， MD PhD（JHU），分枝杆菌学专家; Sabra Klein，PhD（JHU），用于免疫内分泌学培训; Chad Achenbach，MD MPH（NU），用于流行病学，生物统计学和研究设计; Holl，MD 公共卫生硕士（NU），科学写作（赠款和手稿）和演示培训。

ABSTRACT The goal of this Fogarty K43 Global Emerging Leader award is to establish Djeneba Dabitao, PharmD, PhD, as a leading, independent investigator and future mentor in research focused on the role of sex differences in immune responses, disease susceptibility, and treatment outcomes of infectious diseases, particularly in tuberculosis (TB). The field of sex-based biology is rapidly expanding with strong evidence showing that men and women respond differently to microbial challenges, therapeutics, and vaccines. I have chosen to focus on TB because it remains a leading public health problem in poor nations such as Mali in West Africa. Indeed, in this region the incidence of TB in men is, on average, 2 to 3 times higher than women. Yet, despite compelling data indicating that male sex is an independent risk factor for developing active pulmonary TB (TB+), little is known about the underlying mechanisms of increased prevalence in males compared to females. I hypothesize that sex hormones influence CD4+ T cell-mediated immune responses to TB. To test this hypothesis, I will assess differences in immune response between men and women with TB+ (Aim 1) and compare the effects of sex steroid hormones on immune responses between men and women with TB+ ex vivo (Aim 2). The research plan is well aligned with existing, joint research activities between the Université des Sciences, Techniques, et Technologies of Bamako (USTTB) in Mali, Northwestern University (NU) and the Johns Hopkins University (JHU) in the US, which include an R01 on host-pathogen interaction during Mycobacterium africanum infection (R01AI110386; PI: Diallo) and a Fogarty International Center training grant on HIV and mycobacterial diseases (D43TW010350, co-PIs: Diallo and Murphy). I will also leverage the exceptional BSL3 and ImmunoCore facilities and resources, available at the University Clinical Research Center (UCRC), funded by NIAID, under the leadership of Clifford Lane, MD and Seydou Doumbia, MD PhD. For this K43, I will pursue didactic, structured tutorial, and experiential laboratory training to assure acquisition of expertise in four essential areas for me to become a leader in the field of sex differences in disease susceptibility, therapeutics, and potentially vaccine development, namely: (1) immuno-endocrinology, (2) mycobacteriology, (3) epidemiology, biostatistics, and research study design, and (4) grant and manuscript preparation and effective scientific presentation. I have an excellent, multidisciplinary mentoring team of experts from Mali and the US, including Co-Primary Mentors, Souleymane Diallo, MD (USTTB) and Robert Murphy, MD (NU); William Bishai, MD PhD (JHU), expert in mycobacteriology; Sabra Klein, PhD (JHU), for training in immuno-endocrinology; Chad Achenbach, MD MPH (NU), for epidemiology, biostatistics, and research study design; Jane L. Holl, MD MPH (NU), for scientific writing (grant and manuscript) and presentation training.