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GrgA: Key Regulator of Chlamydial Physiology and potential Antichlamydial Target

GrgA：衣原体生理学的关键调节因子和潜在的抗衣原体靶标

基本信息

批准号：
9248878
负责人：
HUIZHOU FAN
金额：
$ 19.39万
依托单位：
RBHS-ROBERT WOOD JOHNSON MEDICAL SCHOOL
依托单位国家：
美国
项目类别：
财政年份：
2016
资助国家：
美国
起止时间：
2016-04-01 至 2019-03-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/9248878
关键词：
Affect Age Alleles Bacteria Biology Cells ChIP-seq Chemicals Chlamydia Chlamydia Infections Chlamydia trachomatis Cytoplasm Defect Development Drug Targeting Ectopic Pregnancy Environment Gene Expression Genes Genetic Recombination Genetic Transcription Genome Goals Grant Growth Growth and Development function High-Throughput DNA Sequencing Housekeeping Human In Vitro Infertility Lactobacillus Medical Metabolic Methods Mutate Mutation Nucleotides Organism Outcome Study Pathogenicity Pelvic Inflammatory Disease Pharmaceutical Preparations Physiology Play Polymerase Predisposition Prevention Probiotics Property Recombinants Regulation Regulon Research Resistance Resolution Role Single Nucleotide Polymorphism Testing Therapeutic Toxic effect Transcriptional Activation Transcriptional Regulation Treatment Efficacy Tube Vacuole Variant Woman Work abortion antimicrobial chromatin immunoprecipitation experimental study extracellular in vivo inhibitor/antagonist insight mutant novel overexpression pathogen peptide deformylase promoter prophylactic public health relevance reproductive therapeutic target transcription factor transcriptome vaginal microbiome

项目摘要

DESCRIPTION (provided by applicant): The goals of this new R21 grant are to determine a) how a novel Chlamydia-specific transcription factor designated GrgA controls chlamydial growth by regulating gene expression, and b) whether GrgA is a target for benzylidene acylhydrazides, which have been recognized as novel antichlamydials. Chlamydia is an obligate intracellular bacterium with a unique developmental cycle. It is the most common sexually transmitted bacterial pathogen. Sexually transmitted chlamydial infection often leads to infertility, abortion, ectopic pregnancy and pelvic inflammatory disease. Transcription not only controls chlamydial growth and pathogenicity, but also represents an effective therapeutic target for chlamydial infections. We have identified a highly novel transcription factor that we call GrgA. Encoded by chlamydiae only, GrgA activates transcription in vitro from promoters that require the primary or housekeeping  factor (a subunit of the RNAP polymerase) designated 66 by interacting with the non-conserved region of the  factor. Further evidence support the hypothesis that GrgA plays a critical role in the regulation of chlamydial growth, and is potentially a target for antichlamydials with therapeutic and prophylactic potentials. We propose two Specific Aims to test this hypothesis. In Aim 1, we will identify the regulon of GrgA, and determine how alterations in the GrgA activity affect the transcriptome expression, and growth and developmental properties in Chlamydia. In Aim 2, we will determine the role of GrgA in chlamydial growth inhibition by benzylidene acylhydrazides, a new group of antichlamydials with undetectable toxicity to host cells and beneficial lactobacilli that dominate the vaginal microbiome of healthy, reproductive-age women. We anticipate three significant outcomes from this study: a) this research will yield insights into transcription regulation in chlamydia; b) we may confirm that GrgA is a target of benzylidene acylhydrazides; and c) with an elucidation of the drug targeting mechanism, benzylidene acylhydrazides could prove valuable as chemical probes for studying chlamydial biology.

描述（由申请人提供）：这项新的 R21 资助的目标是确定 a) 名为 GrgA 的新型衣原体特异性转录因子如何通过调节基因表达来控制衣原体生长，以及 b) GrgA 是否是亚苄基酰肼的靶标，亚苄基酰肼已被认为是新型抗衣原体药物。衣原体是一种专性细胞内细菌，具有独特的发育周期。它是最常见的性传播细菌病原体。性传播的衣原体感染常常导致不孕、流产、宫外孕和盆腔炎。转录不仅控制衣原体的生长和致病性，而且是衣原体感染的有效治疗靶点。我们发现了一种高度新颖的转录因子，我们称之为 GrgA。 GrgA 仅由衣原体编码，通过与 β 因子的非保守区域相互作用，在体外从需要初级或管家 β 因子（RNAP 聚合酶的一个亚基）（称为 β66）的启动子激活转录。进一步的证据支持这样的假设：GrgA 在调节衣原体生长中发挥着关键作用，并且可能是具有治疗和预防潜力的抗衣原体药物的靶点。我们提出两个具体目标来检验这一假设。在目标 1 中，我们将鉴定 GrgA 的调节子，并确定 GrgA 活性的改变如何影响衣原体的转录组表达以及生长和发育特性。在目标 2 中，我们将确定 GrgA 在苯亚甲基酰肼抑制衣原体生长中的作用，苯亚甲基酰肼是一组新的抗衣原体药物，对宿主细胞和有益乳杆菌具有不可检测的毒性，而有益乳杆菌在健康育龄妇女的阴道微生物群中占主导地位。我们预计这项研究将产生三个重要成果：a）这项研究将深入了解衣原体的转录调控； b) 我们可以确认GrgA是亚苄基酰肼的目标； c) 随着药物靶向机制的阐明，苯亚甲基酰肼可以作为研究衣原体生物学的化学探针。