Novel CSF Diagnostics and Genotype Markers of Tuberculous Meningitis in Zambia

描述（由申请人提供）：我是一名在贝斯以色列女执事医疗中心（BIDMC）接受癫痫奖学金培训的董事会认证神经科医生。我现在在赞比亚卢萨卡的赞比亚大学医学院（UNZA-SOM）全职工作。我感兴趣的是最大限度地脑脊液（CSF）诊断艾滋病毒相关的神经系统疾病，并利用这些信息来改善撒哈拉以南非洲地区的患者预后。我建议的研究训练将包括课程作业和教程，重点是发展以下方面的研究技能：(1)神经流行病学，(2)资源有限环境下的实验室诊断，(3)遗传学，(4)神经影像学。通过K23，我将获得在神经传染病领域建立独立研究人员所需的指导研究培训。环境：我组建了一个由三名神经学家组成的指导委员会，他们在全球健康、神经流行病学、神经影像学、遗传学和神经hiv方面具有专业知识。我的主要导师，伊戈尔·科拉尔尼克博士，是一位神经学家，擅长神经hiv和分子诊断。我有两位才华横溢的共同导师，他们在赞比亚有30多年的神经学研究经验：(1)Gretchen Birbeck博士是撒哈拉以南非洲地区全球卫生领域杰出的神经学研究人员；(2) Masharip Atadzhanov博士在神经hiv护理方面具有临床专业知识，在神经遗传学和神经传染病方面有积极的研究项目。我在撒哈拉以南非洲拥有前所未有的实验室和神经成像设备来进行拟议的研究。我有自己的分子诊断实验室是过去三年在联萨援助团som开发的。大学教学医院拥有现代化的计算机断层扫描和磁共振成像设备，已用于积极的研究。我还与赞比亚艾滋病相关结核病项目（ZAMBART）达成了研究合作，该项目被国际公认为是世界上最成熟的艾滋病/结核病研究项目之一。研究计划：结核性脑膜炎（TBM）是赞比亚发病和死亡的主要原因。世界范围内缺乏正确诊断TBM的能力。其结果是，患者往往是经验性的治疗与最小的客观措施，以帮助指导治疗。我们将集中在三个重要领域，以帮助指导TBM的诊断，治疗和预后。首先，我们将尝试通过使用两种用于诊断肺结核的新技术来提高结核性脑膜炎（TBM）的诊断。其次，我们将检查宿主遗传因素，因为它们与生存有关。第三，我们将把宿主遗传因素与

DESCRIPTION (provided by applicant): I am a board-certified neurologist with fellowship training in epilepsy at Beth Israel Deaconess Medical Center (BIDMC). I am now based full-time in Lusaka, Zambia at the University Of Zambia School Of Medicine (UNZA-SOM). I am interested in maximizing cerebrospinal fluid (CSF) diagnostics of HIV- associated neurological diseases and leveraging this information to improve patient outcomes in sub-Saharan Africa. My proposed research training will include coursework and tutorials with a focus on developing research skills in (1) neuroepidemiology, (2) laboratory diagnostics in resource limited settings, (3) genetics, (4) neuroimaging. Through the K23, I will obtain the mentored research training needed to establish myself as an independent researcher in the field of neuroinfectious diseases. The Environment: I have assembled a mentoring committee composed of three neurologists with expertise in global health, neuroepidemiology, neuroimaging, genetics, and Neuro-HIV. My primary mentor, Dr. Igor Koralnik, is a neurologist with expertise in Neuro-HIV and molecular diagnostics. I have two talented co- mentors with more than 30 years of combined experience in neurological research in Zambia: (1) Dr. Gretchen Birbeck is a preeminent neurological researcher in the field of global health in sub-Saharan Africa; (2) Dr. Masharip Atadzhanov has clinical expertise in Neuro-HIV care with active research projects in neurogenetics and neuroinfectious diseases. I have access to unprecedented laboratory and neuroimaging facilities in sub- Saharan Africa to carry out the proposed study. I have my own molecular diagnostic laboratory developed over the last three years at UNZA-SOM. The University Teaching Hospital has modern computed tomography and magnetic resonance imaging units that are already employed in active research. I have also secured research collaboration with the Zambian AIDS Related Tuberculosis (ZAMBART) Project, internationally recognized as one of the most well-established HIV/TB research programs in the world. Research Plan: Tuberculosis meningitis (TBM) is a major cause of morbidity and mortality in Zambia. There is a lack of ability to properly diagnose TBM worldwide. As a result, patients are often treated empirically with minimal objective measures to help guide treatment. We will focus on three important areas to help guide TBM diagnosis, treatment, and prognosis. First, we will attempt to improve the diagnosis of tuberculosis meningitis (TBM) through the use of two novel technologies established for the diagnosis of pulmonary tuberculosis. Second, we will examine host genetic factors as they relate to survival. Third, we will correlate host genetic factors with neuroinflammatory changes seen on neuroimaging. Aim 1: To determine the sensitivity and specificity of Expert MTB/RIF and LAM lateral flow dipstick to diagnose TBM in fresh CSF samples. We will use existing technologies developed for sputum and urine studies to examine the CSF of 550 HIV+ Zambians presenting to the University Teaching Hospital with clinical symptoms concerning for TBM and compare the results to the reference standard of CSF culture. Aim 2: To characterize the impact of LTA4H polymorphisms on survival of Zambian patients with TBM. We will determine if a single nucleotide polymorphism for a gene involved in the neuroinflammatory response to TBM affects survival in 157 patients. Aim 3: To decipher the role of LTA4H genotypes in neuroinflammation in Zambian patients with TBM. We will correlate host genotype for the LTA4H polymorphism with MRI neuroinflammatory findings in 100 TBM patients. These studies will provide objective measures to aid the diagnosis and appropriate treatment of TBM while having a global impact. The findings from this research will build towards future treatment studies that will improve neurological outcomes in TBM patients throughout the world and help me transition into an independent physician scientist.