The effect of mixed-strain M. tuberculosis infections on treatment outcomes

 描述（由申请人提供）：结核病（TB）每年造成130万人死亡，仍然是艾滋病毒感染者死亡的主要原因。应对结核病的威胁将需要采取综合方法，以提高对推动这一流行病的复杂因素的认识。需要在传统流行病学方法和尖端分子方法应用方面具有专门知识的学术学者来填补结核病流行病学知识方面的关键空白。这个指导研究科学家发展奖的目的是支持申相旭博士作为结核病独立研究人员的发展 通过为他提供科学领域的强化培训，他了解了这一全球健康威胁的关键。在获奖期间，Shin博士将完成培训并提交R 01申请，以进行一项关于混合结核分枝杆菌感染的大型前瞻性队列研究。Shin博士的目标是成为结核病和结核病/艾滋病毒合并感染流行病学和预防方面领先的独立大学研究员。他曾接受过流行病学方面的良好培训，并表现出很强的创新学术研究能力。拟议的培训计划是专门设计的，以建立在申博士在全球卫生流行病学的背景，并加强他在结核病相关的具体领域的专业知识。我们将重点关注以下培训主题：1）艾滋病毒和结核病双重感染的流行病学; 2）先进的队列研究方法; 3）分子流行病学;和4）生物信息学。我们将利用正式的课程和研讨会，监督阅读，和实践研究经验，以实现培训目标。Shin博士将在经验丰富的导师的指导和监督下接受培训，这些导师在结核病，艾滋病毒和分子遗传学研究方面有着广泛的记录。 每个导师都有与Shin博士的培训需求相关的互补专业领域。此外，申博士将利用加州大学洛杉矶分校的大量资源，最大限度地提高他的培训经验。加州大学洛杉矶分校在提高与公共卫生直接相关的科学知识方面有着悠久的历史，并将为Shin博士的培训提供一个刺激的环境。申博士将有很好的机会，通过许多研讨会，讲习班和课程向世界知名专家学习。此外，UCLA还在UCLA艾滋病研究所，艾滋病研究中心（CFAR），全球健康计划，基因分型和测序核心以及人类遗传学系的生物信息学核心提供科学专业知识和职业发展机会。申博士设计了一个高度创新的研究方案，以获得上述四个培训领域的实践经验。拟议研究的总体目标是确定混合菌株的影响 M.结核病（MTB）感染对结核病治疗结果的影响。在资源贫乏的国家，超过20%的结核病患者治疗失败、死亡或退出治疗。此外，完成治疗的患者经常有结核病的后续发作。最近的研究表明，一些患者感染了多种MTB菌株（混合MTB感染）。此外，与单一菌株感染的患者相比，混合MTB感染的患者似乎具有更高的治疗效果差的风险。拟议的研究将提供强有力的证据，证明混合型MTB感染是否实际上增加了不良治疗结果的风险。该研究项目的目标1将涉及检查博茨瓦纳结核病患者研究数据库的现有数据。我们将使用现有的MTB基因数据来比较混合型MTB感染患者和单一菌株感染患者之间的不良治疗结果率。对于患者的随机样本，我们将使用最新的基因测序技术检测储存的MTB DNA样本。测序数据将用于确定未检测到的耐药MTB菌株是否是导致混合MTB感染患者治疗结果不佳的原因。至于目的2，我们会进行一个试验组别， 为将来的拨款申请提供初步数据。未来应用程序的目标是 确定混合结核分枝杆菌感染在多大程度上是结核病患者复发的原因， 完成初步治疗。我们将利用博茨瓦纳正在进行的一项大型结核病研究来实施拟议的研究。本研究将通过使用最先进的基因测序技术，显著提高对混合结核分枝杆菌感染的临床效果的理解。研究结果可能直接影响临床和公共卫生实践。鉴于结核病在全球范围内造成的巨大健康负担，拟议的研究对全球健康具有重大意义。这项研究也将成为Shin博士加强其在对应对结核病全球威胁至关重要的科学领域的专业知识的绝佳工具。

 DESCRIPTION (provided by applicant): Tuberculosis (TB) is responsible for 1.3 million deaths annually and remains the leading cause of death among HIV-infected persons. Tackling the threat of TB will require integrated approaches to improve understanding of the complex factors that drive the epidemic. Academic scholars with expertise in conventional epidemiological methods and the application of cutting-edge molecular methods are needed to address critical gaps in knowledge regarding TB epidemiology. The goal of this Mentored Research Scientist Development Award application is to support Dr. Sanghyuk Shin's development as an independent researcher of TB epidemiology by providing him with intensive training in scientific areas that are critical for understanding this global health threat. During the award period, Dr. Shin will complete his training and submit a R01 application to conduct a large, prospective cohort study on the topic of mixed Mycobacterium tuberculosis infections. Dr. Shin's goal is to become a leading independent university-based researcher in the epidemiology and prevention of TB and TB/HIV coinfection. He previously received excellent training in epidemiology and has demonstrated strong capacity to conduct innovative academic research. The proposed training program is uniquely designed to build on Dr. Shin's background in global health epidemiology and to strengthen his expertise in specific areas relevant to TB. We will focus on the following training topics: 1) the epidemiology of dual infection with HIV and TB; 2) advanced cohort study methodology; 3) molecular epidemiology; and 4) bioinformatics. We will utilize formal coursework and workshops, supervised reading, and practical research experience to achieve the training objectives. Dr. Shin will receive his training under the guidance and supervision of seasoned mentors with extensive track records in TB, HIV, and molecular genetics research. Each mentor has complementary areas of expertise relevant to Dr. Shin's training needs. In addition, Dr. Shin will leverage the vast array of resources available at UCLA to maximize his training experience. UCLA has a long history of improving scientific knowledge with direct relevance to public health and will provide a stimulating environment for Dr. Shin's training. Dr. Shin will have excellent opportunities to learn from world renown experts through numerous seminars, workshops, and courses. In addition, UCLA offers scientific expertise and career development opportunities at the UCLA AIDS Institute, Center for AIDS Research (CFAR), Program in Global Health, Genotyping and Sequencing Core, and the Bioinformatics Core of the Department of Human Genetics. Dr. Shin has designed a highly innovative research proposal to gain practical experience in the four training areas described above. The overall goal of the proposed research is to determine the impact of mixed-strain M. tuberculosis (MTB) infections on TB treatment outcomes. In resource-poor countries, over 20% of TB patients fail treatment, die, or drop out of treatment. Furthermore, patients who complete treatment frequently have a subsequent episode of TB. Recent studies have shown that some patients are infected with multiple strains of MTB (mixed MTB infections). Moreover, patients with mixed MTB infections appear to have higher risk for poor treatment outcomes compared to patients with single-strain infections. The proposed research will provide strong evidence on whether mixed MTB infections actually increase the risk for poor treatment outcomes. Aim 1 of the research project will involve examining existing data from a research database of TB patients in Botswana. We will use existing MTB genetic data to compare the rate of poor treatment outcomes between patients with mixed MTB infections and those with single-strain infections. For a random sample of the patients, we will test stored MTB DNA specimens using the latest gene sequencing technology. The sequencing data will be used to determine whether undetected drug-resistant MTB strains are responsible for poor treatment outcomes among patients with mixed MTB infections. For Aim 2, we will conduct a pilot cohort study to generate preliminary data for a future grant application. The goal of the future application is to determine the extent to which mixed MTB infections are responsible for relapse among TB patient who complete their initial treatment. We will take advantage of a large, ongoing TB research study in Botswana to implement the proposed research. This research will significantly improve the understanding of the clinical effect of mixed MTB infection by using state-of-the-art gene sequencing technology. The study findings could directly impact clinical and public health practice. Given the enormous health burden posed by TB worldwide, the proposed research has substantial implications for global health. This research will also serve as an excellent vehicle for Dr. Shin to strengthen his expertise in scientific areas that are critical for addressing the global threat of TB.