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

通过蛋白质组学鉴定分泌型结核分枝杆菌效应子的人类靶标

• 批准号: 8487102
• 负责人: Bennett Penn
• 金额: $ 18.13万
• 依托单位: UNIVERSITY OF CALIFORNIA, SAN FRANCISCO
• 依托单位国家: 美国
• 财政年份: 2013
• 资助国家: 美国
• 起止时间: 2013-07-15 至 2016-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8487102
• 关键词: Aerosols; Affinity; Affinity Chromatography; Agent M; Animal Model; Appointment; Area; Award; Bacterial Proteins; Binding; Biochemical; Bioinformatics; Biological Assay; Cell Culture Techniques; Cells; Chronic; Clinic; Clinical; Communicable Diseases; Data; Data Set; Developmental Biology; Discipline; Disease; Foundations; Genetic; Goals; Health; Human; Immune; Immune response; Immune system; Infection; Integration Host Factors; K-Series Research Career Programs; Knock-out; Knockout Mice; Lead; Mass Spectrum Analysis; Mediating; Medicine; Mentors; Molecular; Mus; Mycobacterium tuberculosis; Pathogenesis; Phenotype; Play; Point Mutation; Positioning Attribute; Post-Translational Protein Processing; Protein Binding; Proteins; Proteomics; Research; Research Personnel; Research Training; Role; Scientist; Series; Techniques; Testing; Training; Tuberculosis; Virulence; Virulence Factors; Virulent; Work; base; functional restoration; genetic manipulation; human disease; immune function; improved; killings; macrophage; novel; novel therapeutics; overexpression; pathogen; professor; protein protein interaction; research study; response; skills; small hairpin RNA; therapy development; tuberculosis treatment

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.

描述（由申请人提供）：这是申请指导的临床科学家研究职业发展奖（K08）Bennett Penn博士，Bennett Penn博士是UCSF的三年级传染病学系，待命为医学教授（辅助系列）。他的长期目标是确定结核分枝杆菌引起人类疾病并根据这些信息开发新的治疗剂的分子机制。该应用的具体目标是结合质谱法（MS）和遗传方法，以识别结核分枝杆菌毒力因子靶向的功能重要的人类蛋白质，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，他使用亲和力纯化和质谱法（MS）来鉴定结核分枝杆菌和人类细胞之间的几百种新型蛋白质 - 蛋白质相互作用。在AIM 1中，他将使用一组生物信息学和生化方法来完善和验证这些MS发现。在AIM 2中，他将使用遗传方法来确定这些相互作用在结核分枝杆菌感染期间起着功能重要的作用。在AIM 3中，这些相互作用的选择将经过详细的生化分析，以建立它们会因破坏宿主免疫功能的分子机制。佩恩博士组建了一支由三名副委员会组成的团队，这些团队桥接了几个学科，以指导他持续的进步。重要的是，由于Penn博士的博士学位工作是在哺乳动物发育生物学领域，因此K08 Award将提供一段其他的研究培训，以获取操纵有毒的结核分枝杆菌和进行MS实验的专业技能。 K08还将为通过UCSF提供的重点课程和研讨会来获取独立研究小组的技能提供更多的支持，并允许Penn博士通过在SFGH TB诊所工作来维持其临床专业化。佩恩博士的完成后，佩恩博士将领导自己的研究小组，并提交R01，进一步扩展了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，从而改善结核病治疗。