Defining the role of site-specific proteolysis in innate defense signaling

定义位点特异性蛋白水解在先天防御信号传导中的作用

• 批准号: 10500999
• 负责人: Mohsan Saeed
• 金额: $ 41.25万
• 依托单位: BOSTON UNIVERSITY MEDICAL CAMPUS
• 依托单位国家: 美国
• 财政年份: 2022
• 资助国家: 美国
• 起止时间: 2022-07-01 至 2027-04-30
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10500999
• 关键词: Acetylation; Award; Cells; Defense Mechanisms; Development; Disease; Environment; Functional disorder; Goals; Human; Innate Immune Response; Invaded; Investigation; Knowledge; Label; Lead; Mission; Molecular Biology; N-terminal; Organ; Pathway interactions; Peptide Hydrolases; Performance; Phosphorylation; Post-Translational Protein Processing; Process; Proteins; Proteolysis; Proteolytic Processing; Regulation; Research; Resolution; Role; Signal Transduction; Site; Systems Biology; Tissues; Toxin; Ubiquitination; United States National Institutes of Health; base; cell growth regulation; defense response; design; experience; improved; insight; microbial; microbial disease; pathogen; potential biomarker; therapeutic target

PROJECT SUMMARY Human cells respond to foreign agents such as pathogens and toxins by initiating a strong innate defense response that creates a protective environment in the cells and incapacitates the invading pathogens and foreign substances. The initiation, activation, and resolution of this innate defense response is a carefully regulated process designed to avoid both hyperactivation and underactivation, either of which can lead to tissue damage, organ dysfunction, and microbial diseases. A key strategy that cells use to achieve tight regulatory control of innate defense signaling is the alteration of protein post-translational modifications (PTMs: phosphorylation, ubiquitination, acetylation, etc.). The goal of my lab for the next five years will be to explore the role of an understudied PTM, the site-specific proteolysis, in regulating innate defense signaling. I have extensive experience in studying antiviral innate immune responses, and have recently optimized a robust protein N-terminal labeling approach that provides an unbiased view of site-specific proteolysis in cells — expertise that will enable me to decipher the regulatory functions of site-specific proteolysis in innate defense mechanisms. With this MIRA award, my group will pursue two specific research directions. First, we will determine the role of the proteolytic N-end rule pathway in controlling the stability of proteins involved in defense signaling. Second, we will investigate the ways in which internal protein cleavages activate defense responses. For the proposed studies, we will employ a combination of focused molecular biology investigations and systems biology approaches, such as activity-based protease profiling and protein N-terminal labeling. These efforts will generate new knowledge about the role of proteases in the regulation of cellular defenses and inform the development of strategies to improve the performance of innate defense mechanisms against escalating microbial and environmental threats.

项目摘要 人类细胞通过启动强大的先天防御来应对病原体和毒素等外来物质 在细胞中创造保护性环境并使入侵病原体丧失能力的反应， 异物。这种先天防御反应的启动、激活和消退是一个非常复杂的过程。 调节过程旨在避免过度活化和活化不足，其中任何一种都可能导致 组织损伤、器官功能障碍和微生物疾病。 细胞用来实现先天防御信号传导的严格调节控制的一个关键策略是改变 蛋白质翻译后修饰（翻译后修饰：磷酸化、遍在蛋白化、乙酰化等）。的目标 在接下来的五年里，我的实验室将探索一种未被充分研究的PTM的作用，即位点特异性蛋白水解， 在调节先天防御信号方面。我在研究抗病毒先天免疫方面有丰富的经验 反应，并最近优化了一个强大的蛋白质N-末端标记的方法，提供了一个 对细胞中位点特异性蛋白质水解的公正看法-专业知识，使我能够破译调控 位点特异性蛋白水解在先天防御机制中的作用。 有了这个MIRA奖，我的团队将追求两个具体的研究方向。首先，我们将确定角色 蛋白水解的N-末端规则途径在控制参与防御信号的蛋白质的稳定性。 其次，我们将研究内部蛋白质裂解激活防御反应的方式。为 建议的研究，我们将采用集中的分子生物学研究和系统相结合， 生物学方法，如基于活性的蛋白酶谱分析和蛋白质N-末端标记。这些努力 将产生关于蛋白酶在细胞防御调节中的作用的新知识，并为蛋白酶的研究提供信息。 制定战略，以提高对升级的先天防御机制的性能 微生物和环境威胁。