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: 9134889
• 负责人: Omar Khalik Siddiqi
• 金额: $ 18.26万
• 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/9134889
• 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; Environment; Epilepsy; European; Exudate; Fellowship; Future; General Population; Genes; Genetic; Genetic Polymorphism; Genotype; Goals; HIV; HIV Infections; Health; 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; Morbidity - disease rate; Neurologic; Neurological outcome; Neurologist; Outcome; Patient-Focused Outcomes; 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; brain parenchyma; experience; global health; improved; insight; interest; leukotriene A4 hydrolase; lipoarabinomannan; molecular diagnostics; mortality; nervous system disorder; nervous system infection; neurogenetics; neuroimaging; neuroinflammation; new technology; novel; novel diagnostics; outcome forecast; programs; 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)：我是贝丝以色列女执事医学中心(BIDMC)癫痫方面的研究员培训委员会认证的神经科医生。我现在在赞比亚卢萨卡的赞比亚大学医学院全职工作。我感兴趣的是最大限度地利用脑脊液(CSF)对艾滋病毒相关神经疾病的诊断，并利用这些信息来改善撒哈拉以南非洲的患者预后。我提议的研究培训将包括课程和教程，重点是培养(1)神经流行病学、(2)资源有限情况下的实验室诊断学、(3)遗传学、(4)神经成像的研究技能。通过K23，我将获得所需的指导性研究培训，以确立自己在神经感染性疾病领域的独立研究员地位。环境：我已经组建了一个指导委员会，由三位神经学家组成，他们在全球健康、神经流行病学、神经成像、遗传学和神经艾滋病毒方面具有专业知识。我的主要导师伊戈尔·科拉尼克博士是一位在神经艾滋病毒和分子诊断学方面有专长的神经科医生。我有两位才华横溢的共同导师，他们在赞比亚有超过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卫生领域的杰出神经学研究员；(2)Masharip Atadzhanov博士在神经艾滋病毒护理方面拥有临床专长，拥有神经遗传学和神经感染性疾病方面的积极研究项目。我可以使用撒哈拉以南非洲史无前例的实验室和神经成像设施来开展拟议的研究。在过去的三年里，我在UNZA-SOM开发了自己的分子诊断实验室。大学教学医院拥有现代计算机断层扫描和磁共振成像设备，这些设备已经用于积极的研究。我还获得了与赞比亚艾滋病相关结核病(赞巴特)项目的研究合作，该项目被国际公认为世界上最成熟的艾滋病毒/结核病研究项目之一。研究计划：结核病脑膜炎(TBM)是赞比亚发病率和死亡率的主要原因。在世界范围内，缺乏正确诊断TBM的能力。因此，患者通常以最小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，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为诊断肺结核而建立的新技术来提高结核病脑膜炎(TBM)的诊断水平。其次，我们将研究与生存相关的宿主遗传因素。第三，我们将宿主遗传因素与 神经影像上可见神经炎性改变。目的：探讨MTB/RIF和LAM侧向流动试纸诊断新鲜脑脊液中脑脊液结核的敏感性和特异性。我们将使用现有的痰和尿液研究技术来检测550名到大学教学医院就诊的有临床症状的HIV阳性赞比亚人的脑脊液，并将结果与脑脊液培养的参考标准进行比较。目的：探讨LTA4H基因多态性对赞比亚结缔组织病患者生存的影响。我们将确定参与TBM神经炎性反应的基因的单核苷酸多态性是否会影响157名患者的生存率。目的：了解LTA4H基因在赞比亚TBM患者神经炎症中的作用。我们将在100例TBM患者中将LTA4H多态的宿主基因型与MRI神经炎性表现相关联。这些研究将提供客观的措施，以帮助诊断和适当的治疗，同时产生全球影响。这项研究的发现将为未来的治疗研究奠定基础，这些研究将改善全世界TBM患者的神经学结果，并帮助我转变为一名独立的内科科学家。