Understanding How the Ubiquitin Ligase CBL Regulates Innate Immune Responses

了解泛素连接酶 CBL 如何调节先天免疫反应

• 批准号: 10468729
• 负责人: Bennett Penn
• 金额: $ 49.31万
• 依托单位: UNIVERSITY OF CALIFORNIA AT DAVIS
• 依托单位国家: 美国
• 财政年份: 2019
• 资助国家: 美国
• 起止时间: 2019-09-19 至 2024-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10468729
• 关键词: Affinity Chromatography; Anti-Bacterial Agents; Antiviral Response; Biochemical; CBL gene; Cells; Complex; Cytokine Activation; Data; Event; Foundations; Future; Genetic; Goals; Growth; Growth Factor Receptors; Health; Host Defense; Human; IRF3 gene; Immune; Immune response; Immune signaling; Immune system; Immunity; Individual; Infection; Innate Immune Response; Integration Host Factors; Interferon-beta; Maps; Mass Spectrum Analysis; Microbe; Molecular; Mus; Mycobacterium tuberculosis; Nucleic Acids; Pathogenesis; Pathway interactions; Pattern recognition receptor; Persons; Phosphorylation; Physiology; Play; Process; Proteins; Proteomics; Regulation; Research Project Grants; Resistance; Role; Serine; Signaling Molecule; Specificity; Testing; Therapeutic; Tuberculosis; United States National Institutes of Health; Vaccines; Variant; Virulence Factors; Virus Diseases; Work; cellular targeting; genetic analysis; immune function; improved; innovation; insight; macrophage; novel; pathogen; response; tuberculosis treatment; ubiquitin ligase; vaccine access

PROJECT SUMMAY/ABSTRACT This is an application for an NIH R01 Research Project Grant. Our long-term goal is to determine how Mycobacterium tuberculosis (Mtb) disrupts the host immune response to establish infection in humans, and to use this information to develop better vaccines and therapies for tuberculosis (TB). In our prior work, we used proteomics to systematically define the interactions between secreted Mtb proteins and human proteins, and discovered a network of several hundred highly-specific interactions that potentially play important roles in Mtb pathogenesis and host defense. We began an initial genetic analysis of the interaction network, and discovered both a novel virulence factor LpqN, as well as its probable host target, the ubiquitin ligase CBL. The specific goal of this application is to study the mechanisms by which CBL regulates innate immune signaling in macrophages and in mice. In Aim 1 we will use biochemical analyses to test the hypothesis that CBL ubiquitylates IRF3 and/or IRF7, targeting them for degradation and thus suppressing antiviral responses. If this hypothesis is incorrect we will take more global approaches to identifying CBL substrates. In Aim 2 we will determine the mechanism by which the virulence factor LpqN disrupts CBL function to promote Mtb growth. In Aim 3 we will explore the function of a novel phosphorylation event we have identified on serine 450 of CBL. These findings will pave the way for future studies that will seek to uncover the molecular mechanisms by which these host factors contribute to immunity and may suggest ways that the factors can be manipulated for therapeutic benefit.

项目总结/摘要 这是NIH R 01研究项目资助的申请表。我们的长期目标是确定 结核分枝杆菌（Mtb）破坏宿主免疫应答以在人类中建立感染，并 利用这些信息来开发更好的结核病疫苗和疗法。在我们之前的工作中，我们使用 蛋白质组学，以系统地定义分泌的Mtb蛋白质和人蛋白质之间的相互作用， 发现了一个由数百种高度特异性相互作用组成的网络，这些相互作用可能在结核病中发挥重要作用。 致病机理和宿主防御。我们开始对互动网络进行初步的遗传分析， 发现了一种新的毒力因子LpqN，以及它可能的宿主靶点，泛素连接酶CBL。的 本申请的具体目标是研究CBL调节先天免疫信号传导的机制 在巨噬细胞和小鼠中。 在目标1中，我们将使用生物化学分析来检验CBL使IRF 3和/或IRF 7泛素化的假设， 靶向它们降解，从而抑制抗病毒反应。如果这个假设是错误的， 采取更多全球性方法来识别CBL底物。 在目标2中，我们将确定毒力因子LpqN破坏CBL功能的机制， 促进结核分枝杆菌生长。在目标3中，我们将探索我们发现的新型磷酸化事件的功能 CBL的丝氨酸450。这些发现将为未来的研究铺平道路， 这些宿主因子有助于免疫的分子机制，并可能提示免疫系统的方式， 可以操纵这些因素以获得治疗益处。