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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

基本信息

批准号：
10680578
负责人：
Bennett Penn
金额：
$ 46.8万
依托单位：
UNIVERSITY OF CALIFORNIA AT DAVIS
依托单位国家：
美国
项目类别：
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/10680578
关键词：
Affinity Chromatography Anti-Bacterial Agents Antibiotics Antiviral Response Biochemical CBL gene Cells Complex Curiosities Data Event Foundations Future Genetic Goals Growth Growth Factor Receptors Health Host Defense Human IRF3 gene Immune Immune Evasion Immune response Immune signaling Immune system Immunity Individual Infection Inflammatory Innate Immune Response Integration Host Factors Interferon-beta Macrophage Maps Mass Spectrum Analysis Microbe Molecular Mus Mycobacterium tuberculosis Nucleic Acids Pathogenesis Pathway interactions Pattern recognition receptor Persons Phosphorylation Physiology Play Probability Process Proteins Proteomics Regulation Research Project Grants Resistance Role Serine Signaling Molecule Specificity Testing Therapeutic Tuberculosis United States National Institutes of Health Vaccines Variant Viral Virulence Factors Virus Diseases Work cellular targeting cytokine genetic analysis immune function improved innovation insight novel pathogen permissiveness response tuberculosis treatment ubiquitin ligase vaccine access

项目摘要

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.

项目摘要/摘要这是 NIH R01 研究项目补助金的申请。我们的长期目标是确定如何结核分枝杆菌 (Mtb) 会破坏宿主免疫反应，从而在人类中建立感染，并导致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，我们使用了蛋白质组学系统地定义分泌的 Mtb 蛋白和人类蛋白之间的相互作用，以及发现了一个由数百个高度特异性相互作用组成的网络，这些相互作用可能在 Mtb 中发挥重要作用发病机制和宿主防御。我们开始对相互作用网络进行初步的遗传分析，并且发现了一种新的毒力因子 LpqN 及其可能的宿主靶标，泛素连接酶 CBL。这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，我们将使用生化分析来检验 CBL 泛素化 IRF3 和/或 IRF7 的假设，针对它们进行降解，从而抑制抗病毒反应。如果这个假设不正确，我们将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 功能的机制促进山地车的增长。在目标 3 中，我们将探索我们已识别的新型磷酸化事件的功能位于 CBL 的丝氨酸 450 上。这些发现将为未来的研究铺平道路，这些研究将寻求揭示这些宿主因子有助于免疫的分子机制，并可能表明可以操纵因素以获得治疗效果。