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：
9018300
负责人：
HUIZHOU FAN
金额：
$ 21.97万
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 2018-03-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/9018300
关键词：
Affect Age Alleles Bacteria Binding 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 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 Vacuole Variant Woman Work abortion antimicrobial chromatin immunoprecipitation extracellular in vivo inhibitor/antagonist insight mutant novel overexpression pathogen peptide deformylase promoter prophylactic public health relevance reproductive research study 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（由适用提供）：这项新的R21赠款的目标是确定a）新型衣原体特异性转录因子如何通过控制基因表达来控制衣原体生长，b）GRGA是否是被识别为已被识别为新型抗裂碱的苯二二烯酰胺的靶标。衣原体是一种具有独特发育周期的义务细胞内细菌。它是最常见的性传播细菌病原体。性传播的衣原体感染通常会导致不育，堕胎，生态妊娠和盆腔炎症性疾病。转录不仅控制衣原体的生长和致病性，而且还代表了衣原体感染的有效治疗靶点。我们已经确定了一个高度新颖的转录因子，我们称之为GRGA。 GRGA仅由衣原体编码，在体外激活了启动子的转录，这些启动子需要通过与因子的非保存区域相互作用，而启动子（RNAP聚合酶的亚基）（RNAP聚合酶的亚基）被指定为66。进一步的证据支持以下假设：GRGA在衣原体生长的调节中起着至关重要的作用，并且可能是具有治疗和预防潜力的抗碱性的靶标。在AIM 1中，我们将确定GRGA的调节，并确定GRGA活性的变化如何影响转录组表达，以及衣原体的生长和发育特性。在AIM 2中，我们将确定GRGA在苄基酰基羟基抑制衣原体生长抑制中的作用，这是一种新的对宿主细胞毒性的新抗植物毒性和有益的乳酸乳杆菌，占主导地位，占主导地位的健康，生殖年龄妇女的阴道微生物组。我们预计这项研究会产生三个重要的结果：a）这项研究将对衣原体的转录调节产生见解； b）我们可能会确认GRGA是苄基酰氢氮酰胺的靶标； c）通过阐明药物靶向机制，苄基酰氢化氮酶可能被证明是研究衣原体生物学的化学问题。