Combinational Regulation of Inflammation in Otitis Media

中耳炎炎症的联合调节

• 批准号: 7850281
• 负责人: Jian-Dong Li
• 金额: $ 25.96万
• 依托单位: UNIVERSITY OF ROCHESTER
• 依托单位国家: 美国
• 财政年份: 2009
• 资助国家: 美国
• 起止时间: 2009-07-17 至 2011-02-28
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7850281
• 关键词: Abbreviations; Bacteria; Bacterial Infections; Cells; Child; Childhood; Complex; Conductive hearing loss; Cytokine Activation; Data; Evolution; Feedback; Figs - dietary; Foundations; Grant; I-kappa B Proteins; In Vitro; Inflammation; Inflammatory; Inflammatory Response; Interleukins; Knockout Mice; Lead; Link; MAPK14 gene; MAPK8 gene; Mediating; Mitogen-Activated Protein Kinase Kinases; Molecular; Myelogenous; N-terminal; NF-kappa B; Nontypable Haemophilus influenza; Nuclear; Otitis Media; Pathogenesis; Patients; Phosphotransferases; Physiological; Play; Polyubiquitin; Principal Investigator; Production; Proteins; Regulation; Relative (related person); Research Personnel; Role; Signal Pathway; Signal Transduction; Small Interfering RNA; Solid; Streptococcus pneumoniae; TNF Receptor-Associated Factors; TNF gene; TRAF6 gene; Tissues; Toll-Like Receptor 2; Toll-like receptors; Tumor Necrosis Factor-alpha; Tumor Necrosis Factors; Tumor Suppressor Proteins; Ubiquitination; cytokine; in vivo; inhibitor/antagonist; insight; middle ear; mutant; new therapeutic target; novel; novel therapeutics; pathogen; prevent; programs; receptor; response

DESCRIPTION (provided by applicant): Otitis media (OM) is the most common childhood bacterial infection and the leading cause of conductive hearing loss in children. Inflammation is a hallmark of OM. Although appropriate inflammatory response triggered by bacteria is essential for eradicating bacterial pathogen, excessive inflammatory response is clearly detrimental to the host due to severe tissue damage. To avoid overactive and detrimental inflammatory response, inflammation must be tightly regulated. Bacteria-induced negative feedback regulation is thought to play a critical role in preventing overactive inflammatory response by inhibiting Toll- like receptor-dependent signaling adaptors. However, the molecular mechanisms underlying the negative feedback regulation of inflammation in the pathogenesis of OM remain unknown. Our Long-term Objective is to understand the molecular mechanisms by which inflammation is induced and regulated in the pathogenesis of OM. During the previous grant period, we focused on investigating the key positive signaling pathways involved in induction of NF-kB-dependent inflammatory response by OM bacterial pathogens including NTHi and S. pneumoniae. Recently we found that CYLD, a newly identified novel deubiquitinase, acts as a negative regulator for NF-kB-dependent inflammatory response induced by NTHi in an autoregulatory feedback manner. Interestingly, CYLD is expressed at low level in middle ear under physiological conditions, but is greatly up-regulated by NTHi. These encouraging preliminary results have thus laid a solid foundation for us to fully investigate the negative feedback regulatory mechanisms by which NTHi-induced NF-kB-dependent inflammation is tightly controlled by CYLD in the pathogenesis of OM in vitro and in vivo (Hypothesis & Short-term Objective). Aim 1. Determine the key receptor-dependent signaling adaptors required for mediating NTHi-induced NF-kB-dependent inflammatory response. Aim 2. Determine the molecular mechanism by which CYLD inhibits NTHi-induced NF-kB-dependent inflammatory response via negative cross-talk with the TRAF6/7 adaptor complex. Aim 3. Determine the molecular mechanisms by which CYLD is induced and regulated by NTHi. Overall, the proposed studies will provide novel insights into the molecular mechanism underlying the tight regulation of inflammation in OM and may lead to new therapeutic strategies for OM patients.

描述（由申请人提供）：中耳炎（OM）是最常见的儿童细菌感染，也是儿童传导性听力损失的主要原因。炎症是 OM 的标志。虽然细菌引发的适当炎症反应对于根除细菌病原体至关重要，但过度的炎症反应显然对宿主有害，因为会造成严重的组织损伤。为了避免过度活跃和有害的炎症反应，必须严格调节炎症。细菌诱导的负反馈调节被认为通过抑制 Toll 样受体依赖性信号转导接头，在预防过度活跃的炎症反应中发挥关键作用。然而，OM 发病机制中炎症负反馈调节的分子机制仍不清楚。我们的长期目标是了解 OM 发病机制中诱导和调节炎症的分子机制。在之前的资助期间，我们重点研究了 OM 细菌病原体（包括 NTHi 和肺炎链球菌）诱导 NF-kB 依赖性炎症反应所涉及的关键正信号通路。最近我们发现CYLD是一种新发现的新型去泛素酶，它以自动调节反馈方式作为NTHi诱导的NF-kB依赖性炎症反应的负调节因子。有趣的是，CYLD在生理条件下在中耳中低水平表达，但被NTHi显着上调。这些令人鼓舞的初步结果为我们在体外和体内 OM 发病机制中全面研究 CYLD 严格控制 NTHi 诱导的 NF-kB 依赖性炎症的负反馈调节机制奠定了坚实的基础 (Hypothesis & Short)术语目标）。目标 1. 确定介导 NTHi 诱导的 NF-kB 依赖性炎症反应所需的关键受体依赖性信号转导接头。目标 2. 确定 CYLD 通过与 TRAF6/7 接头复合物的负串扰抑制 NTHi 诱导的 NF-kB 依赖性炎症反应的分子机制。目标 3. 确定 NTHi 诱导和调节 CYLD 的分子机制。总体而言，拟议的研究将为 OM 炎症严格调节的分子机制提供新的见解，并可能为 OM 患者带来新的治疗策略。