Combinational Regulation of Inflammation in Otitis Media

描述（由申请人提供）：中耳炎（OM）是儿童最常见的细菌感染，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会对宿主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样受体依赖的信号适配器在预防过度活跃的炎症反应中起关键作用。然而，炎症负反馈调控在OM发病机制中的分子机制尚不清楚。我们的长期目标是了解炎症在OM发病过程中诱导和调节的分子机制。在之前的资助期间，我们专注于研究OM细菌病原体（包括NTHi和肺炎链球菌）诱导nf - kb依赖性炎症反应的关键阳性信号通路。最近，我们发现CYLD，一种新发现的新型去泛素酶，以自我调节反馈的方式作为NTHi诱导的nf - kb依赖性炎症反应的负调节因子。有趣的是，生理条件下，CYLD在中耳的表达水平较低，但NTHi会大幅上调CYLD的表达水平。这些令人鼓舞的初步结果为我们在体外和体内充分研究nthi诱导的nf - kb依赖性炎症被CYLD严格控制的负反馈调节机制奠定了坚实的基础（假设&短期目标）。目的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信号转导器。目标2。确定CYLD通过与TRAF6/7接头复合体负向串扰抑制nthi诱导的nf - kb依赖性炎症反应的分子机制。目标3。确定NTHi诱导和调控CYLD的分子机制。总的来说，这些研究将为OM炎症严格调控的分子机制提供新的见解，并可能为OM患者提供新的治疗策略。

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.