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: 8914052
• 负责人: Omar Khalik Siddiqi
• 金额: $ 18.22万
• 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/8914052
• 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; 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; 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; 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）：我是董事会认证的神经科医生，并在贝丝以色列女执事医疗中心（BIDMC）接受了癫痫培训。我现在全职在赞比亚大学医学院（UNZA-SOM）的卢萨卡。我有兴趣最大化脑脊液（CSF）对HIV相关的神经疾病的诊断，并利用此信息来改善撒哈拉以南非洲的患者预后。我提出的研究培训将包括课程和教程，重点是在（1）神经性电子学学，（2）资源有限设置中的实验室诊断中，（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，以确立自己是神经感染疾病领域的独立研究人员。环境：我组建了一个由三位具有全球卫生，神经性电子学，神经影像学，遗传学和神经hiv的神经科组成的指导委员会。我的主要导师伊戈尔·科拉尔尼克（Igor Koralnik）是一位神经科医生，在神经HIV和分子诊断方面具有专业知识。我有两位才华横溢的合作社，在赞比亚有超过30年的神经研究经验：（1）格蕾琴·伯贝克（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博士在神经HIV护理方面拥有临床专业知识，并具有神经遗传学和神经感染疾病的活跃研究项目。我可以使用撒哈拉以南非洲的前所未有的实验室和神经影像学设施来进行拟议的研究。在过去的三年中，我有自己的分子诊断实验室，在UNZA-SOM上。大学教学医院拥有现代的计算机断层扫描和磁共振成像单元，这些单元已经在积极研究中使用。我还确保了与赞比亚艾滋病相关的结核病（Zambart）项目的研究合作，该项目在国际上被认为是世界上最有成熟的HIV/TB研究计划之一。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。缺乏能力在全球范围内正确诊断TBM。结果，经常以最少的客观措施对患者进行治疗，以帮助指导治疗。我们将专注于三个重要领域，以帮助指导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善结核病脑膜炎（TBM）的诊断。其次，我们将检查与生存有关的宿主遗传因素。第三，我们将将宿主遗传因素与 神经影像学上看到的神经炎症性变化。目标1：确定专家MTB/RIF和LAM侧向流动量的灵敏度和特异性，以诊断新鲜CSF样品中的TBM。我们将使用用于痰液和尿液研究开发的现有技术来检查550 HIV+ Zambians向大学教学医院展示的CSF，其临床症状与TBM有关，并将结果与​​CSF文化的参考标准进行比较。目标2：表征LTA4H多态性对赞比亚TBM患者存活的影响。我们将确定针对参与神经炎症反应TBM的基因的单个核苷酸多态性是否会影响157例患者的存活率。目标3：破译LTA4H基因型在赞比亚TBM患者中神经炎症中的作用。我们将在100名TBM患者中将LTA4H多态性的宿主基因型与MRI神经炎症发现相关联。这些研究将提供客观的措施，以帮助对TBM的诊断和适当治疗，同时产生全球影响。这项研究的发现将朝着未来的治疗研究发展，该研究将改善全世界TBM患者的神经系统成果，并帮助我过渡到独立的医师科学家。