Novel CSF Diagnostics and Genotype Markers of Tuberculous Meningitis in Zambia

赞比亚结核性脑膜炎的新型脑脊液诊断和基因型标记

• 批准号: 8789125
• 负责人: Omar Khalik Siddiqi
• 金额: $ 18.44万
• 依托单位: BETH ISRAEL DEACONESS MEDICAL CENTER
• 依托单位国家: 美国
• 财政年份: 2014
• 资助国家: 美国
• 起止时间: 2014-09-01 至 2019-07-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8789125
• 关键词: Accounting; Acquired Immunodeficiency Syndrome; Adjuvant; Adult; Affect; Africa South of the Sahara; African; Alleles; Area; Asians; Brain; CD4 Lymphocyte Count; CD4 Positive T Lymphocytes; Caring; Cell Count; Cells; Central Nervous System Infections; Cerebrospinal Fluid; Clinical; Clinical Management; Collaborations; Cranial Nerves; Data; Diagnosis; Diagnostic; Diagnostic tests; Disease; Eicosanoids; Encephalitis; Environment; Epilepsy; European; Exudate; Fellowship; Future; General Population; Genes; Genetic; Genetic Polymorphism; Genotype; Goals; HIV; HIV Infections; Heterozygote; High Prevalence; Homozygote; Impairment; Inflammation; Inflammatory; Intracranial Hypertension; Israel; Laboratories; Lateral; Leukotriene A4; Life; Magnetic Resonance Imaging; Measures; Medical center; Medicine; Meningeal Tuberculosis; Mentors; Methods; Molecular; Morbidity - disease rate; Neurologic; Neurological outcome; Neurologist; Outcome; Patients; Physicians; Population; Predisposition; Prevalence; Prognostic Factor; Pulmonary Tuberculosis; Recording of previous events; Reference Standards; Research; Research Personnel; Research Project Grants; Research Training; Resources; Rifampicin resistance; Role; Sampling; Schools; Scientist; Secure; Seizures; Sensitivity and Specificity; Signs and Symptoms; Single Nucleotide Polymorphism; Sputum; Steroids; Stroke; Structure; Subarachnoid Space; Symptoms; System; Teaching Hospitals; Technology; Testing; Therapeutic; Time; Training; Treatment Protocols; Tuberculosis; Universities; Urine; X-Ray Computed Tomography; Zambia; base; experience; global health; improved; insight; interest; leukotriene A4 hydrolase; lipoarabinomannan; mortality; nervous system disorder; nervous system infection; neurogenetics; neuroimaging; neuroinflammation; new technology; novel; novel diagnostics; outcome forecast; programs; public health relevance; response; skills

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.

描述（由申请人提供）：我是一名经过委员会认证的神经科医生，在贝斯以色列女执事医疗中心 (BIDMC) 接受过癫痫病专科培训。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利用脑脊液 (CSF) 诊断 HIV 相关神经系统疾病，并利用这些信息来改善撒哈拉以南非洲地区的患者治疗效果。我提议的研究培训将包括课程作业和教程，重点是培养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，我将获得所需的指导研究培训，使自己成为神经传染病领域的独立研究员。环境：我组建了一个指导委员会，由三位在全球健康、神经流行病学、神经影像学、遗传学和神经艾滋病毒领域拥有专业知识的神经学家组成。我的主要导师 Igor Koralnik 博士是一位神经科医生，在神经艾滋病毒和分子诊断方面拥有专业知识。我有两位才华横溢的导师，他们在赞比亚拥有超过 30 年的神经学研究经验：(1) Gretchen Birbeck 博士是撒哈拉以南非洲全球健康领域的杰出神经学研究员； (2) Masharip Atadzhanov 博士拥有神经艾滋病毒护理方面的临床专业知识，并在神经遗传学和神经传染病方面积极开展研究项目。我可以使用撒哈拉以南非洲前所未有的实验室和神经影像设施来开展拟议的研究。我在过去三年里在 UNZA-SOM 建立了自己的分子诊断实验室。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，这些设备已用于积极的研究。我还获得了与赞比亚艾滋病相关结核病 (ZAMBART) 项目的研究合作，该项目被国际公认为世界上最完善的艾滋病毒/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。全世界都缺乏正确诊断 TBM 的能力。因此，患者通常采用最少的客观措施进行经验性治疗，以帮助指导治疗。我们将重点关注三个重要领域来帮助指导 TBM 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改进结核性脑膜炎（TBM）的诊断。其次，我们将检查与生存相关的宿主遗传因素。第三，我们将宿主遗传因素与 神经影像学上观察到的神经炎症变化。目标 1：确定 Expert MTB/RIF 和 LAM 侧流试纸在新鲜脑脊液样本中诊断 TBM 的敏感性和特异性。我们将使用现有的痰液和尿液研究技术来检查 550 名 HIV+ 赞比亚人的脑脊液，这些人因 TBM 相关的临床症状而来到大学教学医院，并将结果与​​脑脊液培养的参考标准进行比较。目标 2：表征 LTA4H 多态性对赞比亚 TBM 患者生存的影响。我们将确定参与 TBM 神经炎症反应的基因的单核苷酸多态性是否会影响 157 名患者的生存。目标 3：破译 LTA4H 基因型在赞比亚 TBM 患者神经炎症中的作用。我们将把 LTA4H 多态性的宿主基因型与 100 名 TBM 患者的 MRI 神经炎症发现相关联。这些研究将提供客观的措施来帮助 TBM 的诊断和适当的治疗，同时产生全球影响。这项研究的结果将为未来的治疗研究奠定基础，这些研究将改善世界各地 TBM 患者的神经系统结果，并帮助我转变为一名独立的医师科学家。