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 蛋白水解酶介导的信号在结核分枝杆菌毒力中的作用 摘要 结核分枝杆菌(Mtb)一直威胁着人类的健康，与结核病(TB)并存。 据估计，每年有100-200万人死亡。不幸的是，分子理解如何 结核分枝杆菌逃避免疫系统不足。知识上的这一关键差距减缓了新技术的设计 寻求提高结核病疫苗效力或提高结核病患者的无菌免疫力的疗法。 我的假设是，当结核杆菌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。我建议探索一种假说，即分泌结核杆菌 蛋白水解酶通过裂解宿主蛋白来促进毒力。我们将使用一种独特的组合 蛋白质组学方法1)确定分泌的Mtb蛋白水解酶的潜在靶点，2)全局 分析结核分枝杆菌感染过程中的蛋白分解事件。然后我将在两个M中使用基因分析。 结核和宿主破坏细菌蛋白水解酶及其可能的宿主底物 目的：探讨蛋白分解在结核病发病机制中的作用。