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: 8700316
• 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/8700316
• 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 Bennett Penn 博士的指导临床科学家研究职业发展奖 (K08) 申请，他是传染病科三年级研究员，即将被任命为 UCSF 医学教授（兼职系列）。他的长期目标是确定结核分枝杆菌引起人类疾病的分子机制，并根据这一信息开发新的治疗方法。该应用的具体目标是结合使用质谱 (MS) 和遗传学方法来识别结核分枝杆菌毒力因子所针对的功能重要的人类蛋白质，并为 Penn 博士领导他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 (MS) 来鉴定结核分枝杆菌和人类细胞之间的数百种新型蛋白质-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完善和验证这些 MS 研究结果。在目标 2 中，他将使用遗传学方法来确定哪些相互作用在结核分枝杆菌感染过程中发挥重要的功能作用。在目标 3 中，将对这些相互作用中的一些进行详细的生化分析，以建立它们破坏宿主免疫功能的分子机制。佩恩博士组建了一个由三名联合导师组成的团队，在多个学科之间架起桥梁，以指导他的持续进步。重要的是，由于 Penn 博士的博士研究领域是哺乳动物发育生物学，K08 奖将提供一段时间的额外研究培训，以获取操纵剧毒结核分枝杆菌和进行 MS 实验的专业技能。 K08 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支持，并将允许 Penn 博士通过在 SFGH 结核病诊所工作来保持其临床专业化。完成该奖项后，Penn 博士将处于领导他自己的研究小组的绝佳位置，并提交 R01，进一步扩展他对结核病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。