权益分类	功能权益	普通用户	{{item.name}}会员
{{category.name}}	{{benefitItem.name}}

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SUMMAY /文摘