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

摘要 Fogarty K43全球新兴领导者奖的目标是建立Djeneba Dabitao，PharmD，PhD， 作为一名领先的、独立的研究人员和未来的导师，他的研究重点是性别差异在 传染病的免疫反应、疾病易感性和治疗结果，特别是在 结核病(TB)。以性为基础的生物学领域正在迅速扩张，强有力的证据表明，男性 女性对微生物挑战、疗法和疫苗的反应也不同。我选择专注于 结核病，因为在西非的马里等贫穷国家，结核病仍然是一个主要的公共卫生问题。事实上，在 这一地区男性的结核病发病率平均是女性的2到3倍。然而，尽管令人信服 数据显示，男性是患活动性肺结核(TB)的独立风险因素，但很少有 了解男性患病率高于女性的潜在机制。我假设 性激素影响CD4T细胞对结核病的免疫反应。为了检验这一假设，我将 评估男性和女性结核病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结核病患者体外免疫反应的影响(目标2)。这项研究 计划与科学、技术等大学现有的联合研究活动很好地结合在一起 马里巴马科(USTTB)、西北大学(NU)和约翰·霍普金斯大学的技术 (JHU)，其中包括关于非洲分枝杆菌感染过程中宿主与病原体相互作用的R01 (R01AI110386；PI：Diallo)和福格蒂国际中心关于艾滋病毒和分枝杆菌疾病的培训赠款 (D43TW010350，共同投资：迪亚洛和墨菲)我还将利用卓越的BSL3和免疫核心 设施和资源，可在大学临床研究中心(UCRC)获得，由NIAID资助，在 Clifford Lane医学博士和Seydou Doumbia博士的领导层。对于这款K43，我将继续说教， 有组织的教程和体验式实验室培训，确保获得四个基本领域的专业知识 对于我来说，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， 生物统计学和研究研究设计，以及(4)赠款和稿件的准备和有效性 科学的陈述。我有一个由马里和美国的专家组成的优秀的、多学科的指导团队， 包括联合小学导师，马里兰州Souley mane Diallo(USTTB)和Robert Murphy，MD(NU)；William Bishai， 医学博士(JHU)，分枝杆菌学专家；Sabra Klein博士(JHU)，免疫内分泌学培训； Chad Achenbach，医学硕士(NU)，流行病学、生物统计学和研究研究设计；Jane L.Holl，医学博士 公共卫生硕士(NU)，用于科学写作(助学金和手稿)和陈述培训。

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.