Identifying the Human Targets of Secreted M. tuberculosis Effectors by Proteomics

描述(由申请人提供)：本尼特·佩恩博士是加州大学旧金山分校传染病系三年级研究员，即将被任命为医学教授(兼职系列)，现申请临床科学家导师研究职业发展奖(K08)。他的长期目标是确定结核分枝杆菌导致人类疾病的分子机制，并基于这些信息开发新的治疗方法。该应用程序的具体目标是结合使用质谱仪(MS)和遗传学方法来识别结核杆菌毒力因子所针对的具有重要功能的人类蛋白质，并为Penn博士领导自己的研究小组获得必要的额外培训。在他的初步研究中，他使用亲和纯化和质谱仪(MS)鉴定了数百种新的结核分枝杆菌和人类细胞之间的蛋白质-蛋白质相互作用。在目标1中，他将使用一套生物信息学和生化方法来提炼和验证这些MS发现。在目标2中，他将使用遗传方法来确定这些相互作用中的哪些在结核分枝杆菌感染过程中起着重要的作用。在目标3中，将对选定数量的这些相互作用进行详细的生化分析，以确定它们的因子扰乱宿主免疫功能的分子机制。潘博士组建了一个由三名共同导师组成的团队，他们在几个学科之间架起了桥梁，为他的持续发展提供指导。重要的是，由于潘博士的博士工作是在哺乳动物发育生物学领域，K08奖将提供一段时间的额外研究培训，以获得操纵致命结核分枝杆菌的专门技能，并进行多发性硬化症实验。K08还将通过加州大学旧金山分校提供的重点课程和研讨会，为获得管理独立研究小组的技能提供额外支持，并将允许Penn博士通过在SFGH TB诊所工作来保持其临床专业性。完成这一奖项后，潘博士将处于一个很好的位置，领导他自己的研究小组，并提交一份R01，进一步扩展他在结核病中宿主与病原体相互作用的研究。 相关性：该项目与人类健康相关，因为了解结核分枝杆菌如何破坏免疫系统将为开发旨在恢复这些功能的疗法奠定基础，从而改善结核病的治疗。

DESCRIPTION (provided by applicant): This is an application for a Mentored Clinical Scientist Research Career Development Award (K08) for Dr. Bennett Penn, a third-year fellow Division of Infectious Diseases with pending appointment as Professor of Medicine (adjunct series) at UCSF. His long-term goal is to determine the molecular mechanisms by which M. tuberculosis causes human disease and to develop new therapeutics based on this information. The specific goal of this application is to use a combination of mass spectrometry (MS) and genetic approaches to identify the functionally important human proteins targeted by M. tuberculosis virulence factors, and to obtain the necessary additional training for Dr. Penn to lead his own research group. In his preliminary studies, he has used affinity purification and mass spectrometry (MS) to identify several hundred novel protein-protein interactions between M. tuberculosis and human cells. In Aim 1, he will use a set of bioinformatics and biochemical approaches to refine and validate these MS findings. In Aim 2, he will use genetic approaches to determine which of these interactions play functionally important roles during M. tuberculosis infection. In Aim 3, a select number of these interactions will be subjected to detailed biochemical analysis to establish the molecular mechanisms by which they factors disrupt host immune function. Dr. Penn has assembled a team of three co-mentors that bridge several disciplines to guide his continued advancement. Importantly, since Dr. Penn's doctoral work was in the field of mammalian developmental biology, the K08 award will provide a period of additional research training to acquire the specialized skills for manipulating virulent M. tuberculosis, and carrying out MS experiments. The K08 will also provide added support for acquiring the skills to manage an independent research group through focused courses and seminars offered by UCSF, and will permit Dr. Penn to maintain his clinical specialization by working at the SFGH TB Clinic. By the completion of this award Dr. Penn will be in an excellent position lead his own research group and to submit an R01 that further extends his studies on host-pathogen interactions in TB. RELEVANCE: This project is relevant to human health because understanding how Mycobacterium tuberculosis disrupts the immune system will lay the foundation for developing therapies aimed at restoring these functions and thereby improving therapy for tuberculosis.