Combinational Regulation of Inflammation in Otitis Media

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。虽然由细菌引发的适当的炎症反应对于根除细菌病原体是必不可少的，但是过度的炎症反应由于严重的组织损伤而明显对宿主有害。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样受体依赖性信号传导衔接子在防止过度活跃的炎症反应中起关键作用。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发病机制中炎症诱导和调节的分子机制。在上一个资助期间，我们重点研究了OM细菌病原体（包括NTHi和S.肺炎。最近我们发现CYLD是一种新发现的去泛素化酶，它以自调节反馈的方式对NTHi诱导的NF-κ B依赖性炎症反应起负调节作用。有趣的是，CYLD在生理条件下在中耳中以低水平表达，但被NTHi大幅上调。因此，这些令人鼓舞的初步结果为我们全面研究NTHi诱导的NF-kB依赖性炎症在体外和体内OM发病机制中受到CYLD严格控制的负反馈调节机制奠定了坚实的基础（假说和短期目标）。目标1.确定介导NTHi诱导的NF-κ B依赖性炎症反应所需的关键受体依赖性信号转导衔接子。目标二。确定CYLD通过与TRAF 6/7衔接子复合物的负串扰抑制NTHi诱导的NF-κ B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。总的来说，拟议的研究将提供新的见解的分子机制的基础上，在OM炎症的严格调节，并可能导致新的治疗策略OM患者。

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.