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

描述（由申请人提供）：这是一个指导临床科学家研究职业发展奖（K 08）的应用程序博士班尼特佩恩，传染病的第三年研究员司与待定任命为医学教授（辅助系列）在加州大学旧金山分校。他的长期目标是确定M。结核病引起人类疾病，并基于此信息开发新的治疗方法。本申请的具体目标是使用质谱（MS）和遗传方法的组合来鉴定M.结核病毒力因子，并获得必要的额外培训，佩恩博士领导自己的研究小组。在他的初步研究中，他使用亲和纯化和质谱（MS）鉴定了M.结核病和人体细胞。在目标1中，他将使用一套生物信息学和生物化学方法来完善和验证这些MS发现。在目标2中，他将使用遗传学方法来确定这些相互作用中哪些在M过程中起重要作用。肺结核感染。在目标3中，将对这些相互作用中的选定数量进行详细的生物化学分析，以建立它们破坏宿主免疫功能的分子机制。Penn博士组建了一个由三位共同导师组成的团队，他们将几个学科联系起来，以指导他继续前进。重要的是，由于Penn博士的博士工作是在哺乳动物发育生物学领域，K 08奖将提供一段时间的额外研究培训，以获得操纵有毒M的专业技能。结核病，并进行MS实验。K 08还将通过UCSF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的支持，并将允许Penn博士通过在SFGH TB诊所工作来保持他的临床专业化。通过完成该奖项，Penn博士将处于一个非常好的位置，领导他自己的研究小组，并提交R 01，进一步扩展他对结核病中宿主-病原体相互作用的研究。 相关性：该项目与人类健康有关，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.