Investigating the Role of Protease-mediated signaling in M. tuberculosis Virulence

研究蛋白酶介导的信号传导在结核分枝杆菌毒力中的作用

• 批准号: 10626147
• 负责人: Bennett Penn
• 金额: $ 18.97万
• 依托单位: UNIVERSITY OF CALIFORNIA AT DAVIS
• 依托单位国家: 美国
• 财政年份: 2022
• 资助国家: 美国
• 起止时间: 2022-06-01 至 2024-05-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10626147
• 关键词: Affinity Chromatography; Amines; Bacteria; Binding; Biochemical; Cells; Data; Enzymes; Event; Foundations; Future; Genetic; Genetic Screening; Genetic study; Goals; Growth; Health; Human; Immune Evasion; Immune response; Immune signaling; Immune system; Immunity; Individual; Inhalation; Integration Host Factors; Isotope Labeling; Knowledge; Macrophage; Maps; Mass Spectrum Analysis; Mediating; Methods; Molecular; Mycobacterium tuberculosis; Natural Immunity; Pathogenesis; Pathway interactions; Patients; Peptide Hydrolases; Persons; Play; Protease Inhibitor; Proteins; Proteolysis; Proteomics; Publishing; Role; Signal Transduction; Specificity; Substrate Interaction; Techniques; Technology; Testing; Tuberculosis; Tuberculosis Vaccines; Vaccination; Virulence; Virulence Factors; Work; design; enzyme substrate; genetic analysis; human pathogen; immune function; improved; mutant; novel; novel therapeutics; pathogen; pathogenic bacteria; therapeutic development; treatment strategy; tuberculosis immunity; tuberculosis treatment; vaccine efficacy

TITLE Investigating the Role of Protease-mediated signaling in M. tuberculosis Virulence ABSTRACT The bacterium M. tuberculosis (Mtb ) persists as a threat to human health, with tuberculosis (TB) killing an estimated 1-2 million people annually. Unfortunately, a molecular understanding of how Mtb evades the immune system is lacking. This critical gap in knowledge slows the design of new therapies that seek to improve TB vaccine efficacy or to promote sterilizing immunity in TB patients. My hypothesis is that when Mtb infects a host macrophage, it deploys proteases to degrade proteins involved in the immune response. I propose to explore the hypothesis that secreted Mtb proteases contribute to virulence by cleaving host proteins. We will use a unique combination of proteomics methods to 1) identify potential targets of secreted Mtb proteases, and to 2) globally profile proteolysis events during Mtb infection. I will then use genetic analysis in both M. tuberculosis and the host to disrupt both the bacterial proteases and their putative host substrates to evaluate the role that proteolysis plays in TB pathogenesis.

标题 研究蛋白酶介导的信号传导在结核分枝杆菌毒力中的作用 抽象的 结核分枝杆菌 (Mtb) 持续威胁人类健康，导致结核病 (TB) 估计每年造成 1-200 万人死亡。不幸的是，分子层面的理解 结核分枝杆菌逃避免疫系统的缺乏。这种知识上的关键差距减缓了新产品的设计 旨在提高结核病疫苗功效或促进结核病患者的绝育免疫力的疗法。 我的假设是，当 Mtb 感染宿主巨噬细胞时，它会部署蛋白酶来降解 参与免疫反应的蛋白质。我建议探索分泌 Mtb 的假设 蛋白酶通过裂解宿主蛋白来产生毒力。我们将使用独特的组合 蛋白质组学方法可 1) 识别分泌型 Mtb 蛋白酶的潜在靶标，以及 2) 在全球范围内 分析 Mtb 感染期间的蛋白水解事件。然后我将在这两个 M 中使用遗传分析。 结核病和宿主破坏细菌蛋白酶及其假定的宿主底物 评估蛋白水解在结核病发病机制中的作用。