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

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

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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.

项目求和/摘要这是NIH R01研究项目赠款的申请。我们的长期目标是确定如何结核分枝杆菌（MTB）破坏了宿主免疫反应以在人类中建立感染，并使用此信息开发出更好的疫苗和结核病疗法（TB）。在我们先前的工作中，我们使用了蛋白质组学系统地定义了分泌的MTB蛋白与人蛋白之间的相互作用，以及发现了数百个高度特定相互作用的网络，该网络可能在MTB中起重要作用发病机理和宿主防御。我们开始对相互作用网络的最初遗传分析，并开始发现了一种新型的毒力因子LPQN及其可能的宿主靶标，泛素连接酶CBL。这该应用的具体目标是研究CBL调节先天免疫信号的机制在巨噬细胞和小鼠中。在AIM 1中，我们将使用生化分析来检验CBL泛素化的假设，即IRF3和/或IRF7，针对它们降解，从而抑制抗病毒反应。如果这个假设不正确，我们将采用更多的全球方法来识别CBL底物。在AIM 2中，我们将确定毒力因子LPQN破坏CBL功能的机制促进MTB增长。在AIM 3中，我们将探索我们已经确定的新型磷酸化事件的功能在CBL的丝氨酸450上。这些发现将为将来的研究铺平道路，以寻求揭示这些宿主因素有助于免疫的分子机制可以为治疗益处操纵因素。