Comprehensive determination of transcription factor location in Francisella

弗朗西斯菌转录因子定位的综合测定

• 批准号: 7869136
• 负责人: SIMON L DOVE
• 金额: $ 25.74万
• 依托单位: BOSTON CHILDREN'S HOSPITAL
• 依托单位国家: 美国
• 财政年份: 2010
• 资助国家: 美国
• 起止时间: 2010-05-06 至 2012-04-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7869136
• 关键词: Biological; Categories; Cells; Coupled; DNA Microarray Chip; Disease; Epitopes; Francisella; Francisella tularensis; Gene Expression; Genes; Genetic Transcription; Genomics; Growth; Hand; Life Style; Location; Molecular; National Institute of Allergy and Infectious Disease; Organism; Pathogenesis; Play; Role; Therapeutic Intervention; Tularemia; Virulence; Work; chromatin immunoprecipitation; density; genome-wide; pathogen; public health relevance; research study; therapeutic development; transcription factor; weapons

DESCRIPTION (provided by applicant): Francisella tularensis, the aetiological agent of tularemia, is one of the most infectious bacterial pathogens currently known and a NIAID category A priority pathogen because of its potential for use as a biological weapon. Unlike many other intracellular pathogenes Francisella encodes relatively few transcription regulators. Although some of these transcription regulators are known to play critical roles in the control of virulence genes required for intracellular survival, for the majority of them it is not known whether they play a role in the control of virulence gene expression. Here we propose to use chromatin immunoprecipitation (ChIP) coupled with fully tiled high density DNA microarrays (ChIP-on-chip) to identify the regulatory targets (i.e. genomic locations) for every predicted transcription regulator in Francisella. In this manner we will be able to (i) understand how certain regulators that are known to play an important role in pathogenesis achieve control over the genes they regulate, (ii) comprehensively determine which subset of the transcription regulators in Francisella are involved in controlling the expression of known virulence genes, and (iii) reveal how any putative connections between the regulatory networks governing virulence gene expression in Francisella allow for the coordinate expression of genes required for intracellular growth. By determining the genomic locations of every transcription factor in Francisella we will be able to define all of the virulence regulatory networks operating in the cell at the level of transcription, and thus identify possible points of therapeutic intervention. PUBLIC HEALTH RELEVANCE: F. tularensis, the causative agent of tularemia, is a potential bioweapon and a NIAID category A priority pathogen. The proposed experiments are expected to reveal how an important intracellular pathogen regulates the expression of genes that are required to cause disease. Our work has implications for the development of therapeutics for the treatment of tularemia.

描述（由申请人提供）：土拉热弗朗西斯菌是土拉热病的病原体，是目前已知最具传染性的细菌病原体之一，并且由于其用作生物武器的潜力而被列为 NIAID A 类优先病原体。与许多其他细胞内病原体不同，弗朗西斯菌编码相对较少的转录调节因子。尽管已知其中一些转录调节因子在控制细胞内存活所需的毒力基因中发挥关键作用，但对于其中的大多数来说，尚不清楚它们是否在控制毒力基因表达中发挥作用。在这里，我们建议使用染色质免疫沉淀 (ChIP) 与完全平铺的高密度 DNA 微阵列 (ChIP-on-chip) 相结合来识别弗朗西斯菌中每个预测转录调节因子的调节靶标（即基因组位置）。通过这种方式，我们将能够（i）了解已知在发病机制中发挥重要作用的某些调节因子如何实现对它们所调节的基因的控制，（ii）全面确定弗朗西斯菌中转录调节子的哪些子集参与控制已知毒力基因的表达，以及（iii）揭示弗朗西斯菌中控制毒力基因表达的调节网络之间的任何假定联系如何允许基因的协调表达 细胞内生长所需的。通过确定弗朗西斯菌中每个转录因子的基因组位置，我们将能够在转录水平上定义细胞中运行的所有毒力调节网络，从而确定可能的治疗干预点。 公共卫生相关性：土拉热杆菌是兔热病的病原体，是一种潜在的生物武器，也是 NIAID A 类优先病原体。拟议的实验有望揭示重要的细胞内病原体如何调节引起疾病所需的基因的表达。我们的工作对兔热病治疗方法的开发具有重要意义。