Biomarker for XDR-TB Treatment Response and Drug Resistance in HIV Endemic Area

描述(由申请人提供)：这份建议书描述了阿尔伯特·爱因斯坦医学院的肺病专家马克斯·奥唐奈博士的职业发展计划和研究建议。奥唐奈博士与爱因斯坦和南非的合作者和导师一起工作，确立了自己在耐药结核病(TB)和艾滋病毒方面的翻译研究员的地位 研究。在南非，耐药结核病引起了更多的警觉，在那里，地方性结核病和艾滋病毒之间的协同作用已导致结核病发病率和病死率“爆炸性”增加。最耐药的结核病形式--广泛耐药结核病(XDR-TB)在南非日益流行。提高广泛耐药结核病存活率的一个重要障碍是缺乏一个快速的生物标志物来作为临床试验的替代结果，并通过测量治疗反应来指导临床医生的治疗。荧光分枝杆菌噬菌体(FMP)检测使用转基因分枝杆菌特异性病毒，使用荧光报告系统定量检测活的结核分枝杆菌(Mtb)。O‘Donnell博士利用一种具有优越测试特性的新的FMP分析方法，建议测量广泛耐药结核病患者痰中结核分枝杆菌的减少，作为治疗反应的生物标记(目标1)。在治疗无效的广泛耐药结核病患者中，O‘Donnell博士建议使用相同的检测方法来快速诊断紧急的二线耐药(目标2)。本提案的这一研究部分是阿尔伯特·爱因斯坦医学院的研究人员与夸祖鲁-纳塔尔结核病和艾滋病毒/艾滋病研究所(K-RITH)和南非艾滋病研究中心(CAPRISA)的研究人员正在资助的合作的结果。这项建议的培训内容包括将申请者培养为结核病分子流行病学家，包括导师实验室的培训、课程作业、研讨会、讲座和耐药结核病微生物学方面的专门培训。独一无二的特色包括来自著名结核病基础科学家、结核病流行病学家和翻译研究员的共同指导，以及具有广泛结核病和职业发展经验的职业发展委员会的额外支持。这是一种创新的方法，有可能对我们合理管理耐药结核病的能力产生实质性影响，快速评估比较疗效 不同的药物方案，并在治疗过程中快速诊断结核病患者的紧急耐药。这项研究将为临床生物标记物在耐药结核病治疗结果中的应用的前瞻性研究奠定基础，该研究将在K奖结束前提出的R01拨款申请中提出。

DESCRIPTION (provided by applicant): This proposal describes a career development plan and research proposal for Dr. Max O'Donnell, a pulmonologist at Albert Einstein College of Medicine. Working with collaborators and mentors at Einstein and in South Africa, Dr. O'Donnell is establishing himself as a translational investigator in drug-resistant tuberculosis (TB) and HIV research. Nowhere has drug-resistant TB generated more alarm than in South Africa, where synergies between endemic TB and HIV have caused 'explosive' increases in TB incidence and case-fatality rates. The most resistant form of TB, extensively drug resistant tuberculosis (XDR-TB), is increasingly prevalent in South Africa. An important obstacle to improving survival for XDR-TB is lack of a rapid, biomarker to serve as a surrogate outcome in clinical trials and guide clinician's by measuring treatment response. Fluoromycobacteriophage (FMP) assays use genetically modified mycobacteria-specific viruses to quantify viable M tuberculosis (Mtb) using a fluorescence reporter system. Utilizing a novel FMP assay with superior test characteristics, Dr. O'Donnell proposes to measure decrease in Mtb in XDR-TB patients' sputum as a biomarker for treatment response (Aim 1). Among XDR-TB patients who fail to respond to treatment Dr. O'Donnell proposes to use the same assay to rapidly diagnose emergent second-line drug resistance (Aim 2). This research component of this proposal is a result of an ongoing funded collaboration between researchers at Albert Einstein College of Medicine with researchers at the KwaZulu-Natal Research Institute for Research in Tuberculosis and HIV/AIDS (K-RITH), and the Centre for AIDS Programme of Research in South Africa (CAPRISA). The training component of this proposal involves developing the applicant as a TB molecular epidemiologist including training in the mentor's laboratory, coursework, seminars, lectures, and specific training in drug-resistant TB microbiology. Unique features include co-mentoring from a renowned TB basic scientist, TB epidemiologist, and translational researcher with additional support from career development committee with extensive TB and career development experience. This is an innovative approach with the potential to make substantial impact in our ability to rationally manage drug-resistant tuberculosis, rapidly evaluate the comparative efficacy of different drug regimens, and rapidly diagnose emergent drug-resistance among TB patients on treatment. This research will form the basis for a prospective study of the application of clinical biomarkers for treatment outcome in drug-resistant tuberculosis that will be proposed in an R01 grant application before the end of the K award.