Toll-like Receptor 2, Vitamin D, and Extrapulmonary Tuberculosis

描述（由申请人提供）：结核病（TB）是一种全球性的卫生紧急情况。世界卫生组织估计，2007年全世界约有930万人被诊断患有结核病，200万人死亡。结核病代表了一个有趣的悖论：虽然估计世界人口的三分之一感染了结核分枝杆菌，但只有5-10%的感染者继续发展为结核病的临床表现。肺外结核可能是潜在免疫功能受损的标志。候选人的导师进行的研究表明，与以前患有肺结核和潜伏性M的人相比，以前患有肺外结核的人似乎有先天性免疫缺陷。肺结核感染。进一步研究肺外结核患者的免疫反应，可以提供使人从潜伏性结核病发展为结核病的免疫因素的线索。结核病感染的临床疾病，并有助于结核病的预防工作，确定结核病疫苗的潜在目标。新出现的证据表明，病原体识别受体称为Toll样受体（TLR），特别是TLR 2和维生素D在对M的免疫应答中起主要作用。结核在本研究中，将解决两个特定目的：（1）评估既往肺外TB患者中TLR 2的数量和功能，以及（2）测量既往肺外TB患者中维生素D受体和维生素D介导的免疫激活的数量和功能。将使用聚合酶链反应（PCR）和流式细胞术进行数量和功能测量。结果将与既往肺结核患者、潜伏性M。结核感染者和未感染结核分枝杆菌的健康对照者。结核病（PPD阴性）。将使用巨噬细胞刺激和M感染的体外模型研究目的。结核 候选人在临床研究方面有很强的背景，获得了公共卫生硕士学位，并完成了几项结核病流行病学研究。这个奖项将支持她，而她实现她的短期职业目标，扩大她的免疫反应的知识，以M。结核病，同时建立了坚实的基础，从实现她的长期目标，成为一个独立的和富有成效的翻译研究的翻译免疫学研究。她的两个主要职业发展目标是：（1）加强她现有的知识，并获得免疫学和转化研究的新专业知识;（2）完善她在手稿和赠款中的科学写作技能，通过NIH的RO 1资金成功竞争长期研究支持。候选人计划通过在实验室进行实践培训，参加高级免疫学和研究技能的几门教学课程，以及参加国家和国际科学会议来增强她的免疫学和研究技能，这将有利于与有共同兴趣的研究人员建立网络和合作。她将通过科学写作教学课程以及参加范德比尔特大学医学中心的写作研讨会和内部资助审查机制来实现她的第二个目标。 她在范德比尔特大学医学中心的环境有利于她的愿望。Timothy Sterling博士是国际公认的结核病研究领域的专家，他成功地指导了年轻的医生科学家，他们已经在学术医学领域从事富有成效的研究工作，并拥有可用的资源来支持她的研究工作。她的共同导师Spyros Kalams博士是一位有成就的免疫学家，并在免疫学实验室提供指导。她还得到了一个委员会的指导，该委员会由范德比尔特非常成功的基础和翻译研究人员组成，他们具有不同的研究兴趣，这将有助于指导她的职业发展。候选人可利用的资源包括最先进的实验室设施和设备以及具有先进技术的核心实验室。除了技术资源外，候选人还可以访问范德比尔特大学医学中心的独特资源，这些资源由临床和转化科学奖（CTSA）提供，如临床研究中心，范德比尔特临床和转化研究所以及临床和转化科学家发展计划，CTSA的教育部分。该大学通过范德比尔特医生科学家发展计划（VPSD）支持她，表现出对候选人的投资兴趣，VPSD是一个竞争性的校内资助机制，是通往校外资助（即K奖）的“桥梁”。 目前的提案对结核病预防和疫苗学领域具有重要意义，该奖项将使候选人能够建立在临床结核病研究的坚实基础上，发展转化研究的新技能，并过渡到职业生涯的下一阶段。 项目简介：结核病是一个全球性的紧急情况。我们对人类对结核分枝杆菌的保护性免疫反应的理解是不完整的。免疫反应的进一步表征可以帮助识别从M进展的人。结核感染到活动性疾病。这些知识将对结核病疫苗的开发和结核病预防工作产生重大影响。

DESCRIPTION (provided by applicant): Tuberculosis (TB) is a global health emergency. The World Health Organization estimated that approximately 9.3 million people worldwide were diagnosed with TB in 2007 and 2 million persons died. TB represents an interesting paradox: while one-third of the world's population is estimated to be infected with Mycobacterium tuberculosis, only 5-10% of infected persons go on to develop clinical manifestations of TB. Extrapulmonary TB is likely a marker of underlying immune compromise. The candidate's mentor has performed studies showing that persons with previous extrapulmonary TB appear to have an innate immune defect compared to persons with previous pulmonary TB and latent M. tuberculosis infection. Further study of the immune response of persons with previous extrapulmonary TB could provide clues to the immune factors that predispose a person to progress from latent M. tuberculosis infection to clinical disease and contribute to TB prevention efforts by identifying potential targets for TB vaccines. Emerging evidence suggests that pathogen recognition receptors called Toll-like receptors (TLRs), specifically TLR2, and vitamin D play a major role in the immune response to M. tuberculosis. In this study, two Specific Aims will be addressed: (1) to evaluate the quantity and function of TLR2 in persons with previous extrapulmonary TB and (2) to measure the quantity and function of the vitamin D receptor and vitamin-D mediated immune activation in persons with previous extrapulmonary TB. Measurements of quantity and function will be performed using polymerase chain reaction (PCR) and flow cytometry. Results will be compared to results obtained from persons with previous pulmonary TB, persons with latent M. tuberculosis infection, and healthy controls who are not infected with M. tuberculosis (PPD negative). The Aims will be investigated using an in vitro model of macrophage stimulation and infection with M. tuberculosis. The candidate has a strong background in clinical research, having obtained her Masters of Public Health and completed several TB epidemiologic studies. This award will support her while she achieves her short term career goal of expanding her knowledge of the immune response to M. tuberculosis, while establishing a strong foundation in translational immunologic research from which to attain her long term goal of becoming an independent and productive translational investigator. Her two primary Career Development Aims are: (1) to strengthen her existing knowledge and acquire new expertise in immunology and translational research and (2) to refine her scientific writing skills in manuscripts and grants to successfully compete for long-term research support through RO1 funding from NIH. The candidate plans to augment her immunology and research skills through hands-on training in the laboratory, participation in several didactic courses in advanced immunology and research skills, and attendance of national and international scientific meetings which will be favorable for networking and collaborating with investigators with shared interests. She will achieve her second Aim through didactic coursework in scientific writing as well as participation in available writing workshops and internal grant review mechanisms available at Vanderbilt University Medical Center. Her environment at Vanderbilt University Medical Center is conducive to her aspirations. She is supported by her primary mentor, Dr. Timothy Sterling, who is an internationally recognized expert in the area of TB research, has successfully mentored young physician-scientists who have gone on to productive research careers in academic medicine, and has the resources available to support her research efforts. Her co-mentor, Dr. Spyros Kalams, is an accomplished immunologist and has provided guidance in the immunology lab. She also is mentored by a committee consisting of highly successful basic and translational researchers at Vanderbilt with diverse research interests who will help guide her career development. The resources available to the candidate include state-of-the-art laboratory facilities and equipment as well as core laboratories with advanced technology. In addition to technical resources, the candidate has access to unique resources at Vanderbilt University Medical Center made possible by the Clinical and Translational Science Award (CTSA) such as the Clinical Research Center, the Vanderbilt Institute for Clinical and Translational Research, and the Clinical and Translational Scientist Development program, the educational component of the CTSA. The university has shown invested interest in the candidate by supporting her through the Vanderbilt Physician Scientist Development Program (VPSD), a competitive intramural funding mechanism that serves as a "bridge" to extramural funding (ie K award). The current proposal has important implications to the field of TB prevention and vaccinology, and this award will allow the candidate to build on her strong foundation of clinical TB research and develop new skills in translational research and transition to the next phase of her career. Project Narrative: Tuberculosis is a global emergency. Our understanding of the human protective immune response to Mycobacterium tuberculosis, the causative agent of tuberculosis is incomplete. Further characterization of the immune response could help identify persons who progress from M. tuberculosis infection to active disease. This knowledge would have significant implications for tuberculosis vaccine development and tuberculosis preventive efforts.