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Elucidating the Sensing Abilities of Virulence Regulatory Systems

阐明毒力调节系统的感知能力

基本信息

批准号：
10452800
负责人：
Eduardo Groisman
金额：
$ 53.99万
依托单位：
YALE UNIVERSITY
依托单位国家：
美国
项目类别：
财政年份：
2021
资助国家：
美国
起止时间：
2021-08-05 至 2022-07-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10452800
关键词：
Algorithms Anti-Bacterial Agents Antibiotics Antimicrobial Resistance Bacteria Bacterial Drug Resistance Bacterial Physiology Binding Binding Proteins Binding Sites Biochemical Biological Cell physiology Cells ChIP-seq Code DNA DNA Sequence Disease Ensure Enzymes Equilibrium Evaluation Fluorescence Gastroenteritis Gene Activation Genes Genetic Genetic Transcription Genome Grant Histones Human Infection Life Style Measures Mediating Messenger RNA Methodology Methods Molecular Molecular Chaperones Mus Open Reading Frames Pathogenesis Physiological Post-Transcriptional Regulation Process Promoter Regions Property Proteins Proteome RNA RNA Binding RNA-Binding Proteins Research Role Salmonella Salmonella typhimurium Signal Transduction Site Stress Structural Protein Superhelical DNA System Tissues Transcription Coactivator Transcription Initiation Typhoid Fever Virulence Virulence Factors antimicrobial drug cell envelope experience genome-wide in vivo macrophage microorganism novel pathogen pathogenic bacteria programs response sensor success transcription factor transmission process

项目摘要

PROJECT SUMMARY Bacterial pathogens exert tight control over their proteomes. This proposal examines how Salmonella enterica serovar Typhimurium exerts this control. It makes direct use of novel methods and conceptual breakthroughs developed during the last grant period. First, we will identify genes that govern global DNA supercoiling using Fluorescence Evaluation of DNA Supercoiling, a novel high throughput method that examines DNA supercoiling in living cells. We will then investigate how the identified genes control this essential process. Second, we will explore the mechanism by which the master virulence regulator PhoP promotes transcription of an open reading frame when binding to that very same open reading frame. These unusually located PhoP binding sites were uncovered with Identification of Transcription Factor Sites, a novel algorithm that captures transcription factor binding sites genome wide and overcomes the limitations of SELEX and ChIP-seq. And third, we will determine the post- transcriptional mechanisms by which the RNA chaperone CspC and the novel small protein UgtS control the abundance and activity of the virulence protein UgtL. The proposed research will provide a molecular understanding of cellular physiology and likely be broadly applicable because all bacteria supercoil their DNA, activate gene transcription, and exert post-transcriptional control of their genes.

项目概要细菌病原体对其蛋白质组进行严格控制。该提案审查了肠沙门氏菌鼠伤寒血清型如何发挥这种控制作用。它直接利用在上一个资助期间开发了新的方法和概念突破。首先，我们将使用荧光识别控制全局 DNA 超螺旋的基因 DNA 超螺旋的评估，一种检查 DNA 的新型高通量方法活细胞中的超螺旋。然后我们将研究已识别的基因如何控制这个重要的过程。其次，我们要探讨master的机制。毒力调节因子 PhoP 促进开放阅读框的转录与同一个开放阅读框结合。这些异常定位的 PhoP 结合通过转录因子位点识别（一种新算法）发现了位点捕获全基因组转录因子结合位点并克服 SELEX 和 ChIP-seq 的局限性。第三，我们将确定后 RNA伴侣CspC和新型小分子的转录机制 UgtS 蛋白控制毒力蛋白 UgtL 的丰度和活性。这拟议的研究将提供对细胞生理学的分子理解可能广泛适用，因为所有细菌都将其 DNA 超螺旋，激活基因转录，并对它们的基因进行转录后控制。