Bacterial AHL interactions with nuclear receptors

细菌 AHL 与核受体的相互作用

• 批准号: 6906415
• 负责人: Barry M. Forman
• 金额: $ 8.6万
• 依托单位: BECKMAN RESEARCH INSTITUTE/CITY OF HOPE
• 依托单位国家: 美国
• 财政年份: 2004
• 资助国家: 美国
• 起止时间: 2004-07-01 至 2007-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6906415
• 关键词: Agrobacterium; Agrobacterium tumefaciens; Escherichia coli; Pseudomonas aeruginosa; Salmonella typhimurium; Vibrio; bacteria infection mechanism; biofilm; biological signal transduction; butyrolactone; chronic disease /disorder; drug resistance; eukaryote; gel mobility shift assay; gene expression; genetic transcription; host organism interaction; intermolecular interaction; ligands; nuclear receptors; pathologic process; peroxisome proliferator activated receptor; polymerase chain reaction; receptor binding; transcription factor; transfection

DESCRIPTION (provided by applicant): Free-living bacteria tend to associate with cell or inert surfaces to form surface-associated communities called biofilms. Gram-negative bacteria release small molecules called acyl homoserine lactones (AHLs) into the surrounding environment to communicate within and between species. When sufficient bacteria are present to form a "quorum," the AHLs reach high enough concentrations to trigger developmental programs that change the morphology and biochemical functionality of the cells to adapt them to life in a biofilm community. Among the changes incurred by this so-called quorum sensing system are loss of motility and gain of antibiotic resistance. Biofilms associated with chronic lung infections in cystic fibrosis and septic infections related to medical device implantation are difficult to eradicate with antibiotic therapy due to induction of resistance genes in the biofilm members. Persistent biofilms or bacterial overgrowths that are difficult to eradicate may produce large quantities of these AHLs. Recent evidence suggests that AHLs interact with eukaryotic cell signaling systems and can alter host gene expression. Preliminary molecular modeling suggests that AHLs may be able to bind to the human peroxisome proliferator-activated receptor gamma (PPARg), a nuclear receptor with important roles in inflammation, obesity, diabetes, and cardiovascular disease that binds a number of small molecule ligands. There is no data either in vitro or in vivo demonstrating whether AHLs in fact bind to eukaryotic nuclear receptors and alter gene transcription. We propose to determine whether bacterially derived AHLs can regulate eukaryotic gene transcription by activating host nuclear receptors including the PPARs, LXRs, FXR, CAR, PXR/SXR, ERs, TRs, and VDR.

描述（由申请人提供）：自由生活的细菌倾向于与细胞或惰性表面结合，形成称为生物膜的表面相关群落。革兰氏阴性细菌将称为酰基高丝氨酸内酯 (AHL) 的小分子释放到周围环境中，以在物种内部和物种之间进行交流。当存在足够的细菌形成“群体”时，AHL 达到足够高的浓度以触发发育程序，改变细胞的形态和生化功能，以适应生物膜群落中的生活。这种所谓的群体感应系统引起的变化包括运动性的丧失和抗生素耐药性的增加。由于生物膜成员中诱导了耐药基因，与囊性纤维化中的慢性肺部感染和医疗器械植入相关的化脓性感染相关的生物膜很难用抗生素治疗根除。难以根除的持续生物膜或细菌过度生长可能会产生大量的 AHL。最近的证据表明 AHL 与真核细胞信号系统相互作用并可以改变宿主基因表达。初步分子模型表明，AHL 可能能够与人过氧化物酶体增殖物激活受体 γ (PPARg) 结合，PPARg 是一种核受体，在炎症、肥胖、糖尿病和心血管疾病中发挥重要作用，可结合许多小分子配体。没有体外或体内数据证明 AHL 是否确实与真核核受体结合并改变基因转录。我们建议确定细菌来源的 AHL 是否可以通过激活宿主核受体（包括 PPAR、LXR、FXR、CAR、PXR/SXR、ER、TR 和 VDR）来调节真核基因转录。