CYLD as a negative regulator for MUC5AC in NTHi-induced otitis media

CYLD 作为 NTHi 诱发的中耳炎中 MUC5AC 的负调节因子

• 批准号: 7329655
• 负责人: Erika A Szymanski
• 金额: $ 0.65万
• 依托单位: UNIVERSITY OF ROCHESTER
• 依托单位国家: 美国
• 财政年份: 2007
• 资助国家: 美国
• 起止时间: 2007-12-01 至 2008-01-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7329655
• 关键词: Address; Antibiotic Therapy; Antibiotics; Bacterial Infections; Binding Sites; Cellular biology; Child; Childhood; Clinical Management; Complex; Conductive hearing loss; Data; Development; Disease; Enzymes; Epithelial Cells; Escalator; Family; Feedback; Figs - dietary; Foundations; Glycoproteins; Goals; Haemophilus Vaccines; Haemophilus influenzae; Healthcare; Hearing problem; Human; Immune response; In Vitro; Infection; MAPK14 gene; MAPK8 gene; MUC5AC gene; Mediating; Modeling; Molecular; Molecular Target; Mucins; Mucous body substance; Nontypable Haemophilus influenza; Numbers; Otitis Media; Pain; Pathway interactions; Pharmaceutical Preparations; Physicians; Physiological; Process; Production; Regulation; Role; Signal Pathway; Signal Transduction; Signal Transduction Pathway; Societies; Structure of respiratory epithelium; Symptoms; TLR2 gene; TNF receptor-associated factor 6; TRAF6 gene; Techniques; Testing; Transcription Factor AP-1; Transcriptional Regulation; Tumor Suppressor Proteins; Ubiquitination; Up-Regulation; Visit; Work; base; cell type; ear infection; in vivo; middle ear; novel; novel therapeutics; pathogen; pediatrician; prescription document; prescription procedure; respiratory; tumor

DESCRIPTION (provided by applicant): Otitis media is responsible for substantial human suffering, the most common reason for pediatric physician visits and antibiotic prescriptions to children, and the cause of over $5 billion in health care expenses annually. Initial infection by bacterial pathogens including non-typeable Haemophilus influenzae (NTHi) is believed to contribute to most otitis media. Bacterial infection directly provokes pain and conductive hearing loss by stimulating mucus overproduction in the middle ear. Mucus is largely the product of mucin glycoproteins including MUC5AC, which is strongly upregulated by bacterial infection. The signaling pathways through which NTHi induces MUC5AC are relatively well-characterized. In contrast, signaling pathways through which NTHi-induced MUC5AC expression is down-regulated remain essentially unknown. The goal of this proposed study is to examine the role of CYLD, the cylindromatosis tumor supressor, in regulating MUC5AC expression in the context of NTHi-induced otitis media. CYLD is a deubiquitinase enzyme shown to negatively regulate multiple signaling pathways, including the p38 pathway principally involved in MUC5AC upregulation. We therefore hypothesize that CYLD negatively regulates NTHi-induced MUC5AC expression by deubiquitinating TRAF6 and/or TRAF7, signaling intermediates of the p38 pathway. By elucidating how mucus production is down-regulated, we will facilitate the development of novel therapeutics that reduce mucus overproduction in the middle ear and thereby ameliorate the symptoms and sequelae of otitis media. Using multiple molecular and cell biology techniques, we will: 1. Investigate the inhibitory effect of CYLD on NTHi-induced MUC5AC expression in models of otitis media in vitro and in vivo. 2. Identify the molecular targets of CYLD involved in the CYLD-mediated regulation of NTHi-induced MUC5AC expression in vitro and in vivo. 3. Determine the molecular mechanism through which CYLD regulates NTHi-induced MUC5AC expression. Ear infections are the number one reason for visits to pediatricians and antibiotic prescriptions to children, and a major cause of human suffering. Excess mucus production triggered by bacterial infection leads to pain and short- and long-term hearing problems during ear infections. Understanding how mucus production is controlled in the middle ear will lay the foundation for new drugs that decrease mucus production and make ear infections less harmful.

描述（由申请人提供）：中耳炎是造成大量人类痛苦的原因，是儿科医生就诊和儿童抗生素处方的最常见原因，也是每年超过50亿美元医疗保健费用的原因。最初感染的细菌病原体，包括非分型流感嗜血杆菌（NTHi）被认为有助于大多数中耳炎。细菌感染通过刺激中耳中粘液的过度产生直接引起疼痛和传导性听力损失。粘液主要是粘蛋白糖蛋白的产物，包括MUC 5AC，其被细菌感染强烈上调。NTHi诱导MUC 5AC的信号传导途径是相对良好表征的。相比之下，NTHi诱导的MUC 5AC表达下调的信号通路基本上仍然未知。本研究的目的是研究CYLD（圆柱瘤病肿瘤抑制剂）在NTHi诱导的中耳炎中调节MUC 5AC表达的作用。CYLD是一种去泛素化酶，可负调节多种信号通路，包括主要参与MUC 5AC上调的p38通路。因此，我们假设CYLD通过去泛素化TRAF 6和/或TRAF 7（p38通路的信号传导中间体）负性调节NTHi诱导的MUC 5AC表达。通过阐明粘液产生是如何下调的，我们将促进新的治疗方法的发展，减少中耳粘液过度产生，从而改善中耳炎的症状和后遗症。使用多种分子和细胞生物学技术，我们将：1。在体外和体内研究CYLD对NTHi诱导的MUC 5AC表达的抑制作用。2.鉴定参与CYLD介导的NTHi诱导的MUC 5AC体外和体内表达调节的CYLD分子靶标。3.确定CYLD调节NTHi诱导的MUC 5AC表达的分子机制。耳部感染是儿科医生就诊和儿童抗生素处方的首要原因，也是人类痛苦的主要原因。由细菌感染引发的过量粘液产生导致耳朵感染期间的疼痛和短期和长期听力问题。了解中耳中粘液的产生是如何控制的，将为减少粘液产生和降低耳部感染危害的新药奠定基础。