Combinational regulation of inflammation in otitis media

描述(申请人提供)：肺炎链球菌(肺炎链球菌)和非分型流感嗜血杆菌(NTHi)是引起中耳炎(OM)的主要人类病原体。炎症是OM的特征。然而，OM炎症的分子机制仍不清楚。我们的长期目标是了解炎性反应是如何在OM的发病机制中诱导和调节的。鉴于在体情况下，多种因素同时存在，高达24-48%的OM患者合并肺炎链球菌和NTHi感染，我们假设在OM的发病机制中，NF-kB是由多个致病诱导因子通过激活多个信号通路协同调节的(总体假设)。事实上，我们的初步结果表明，NTHi和肺炎链球菌或NTHi和TNF-α通过涉及IKBcz、p38MAPK和MEKK1的多个信号通路协同激活NF-kB和细胞因子的产生。因此，这些令人鼓舞的结果为进一步研究多种致病诱导因子激活和细胞因子产生的信号机制奠定了坚实的基础(短期目标)。目的1.通过干扰转化生长因子-β-Smad信号通路的信号传导，确定转化生长因子-β-Smad信号通路是否以及如何参与NTHi诱导的核因子-kB的激活和细胞因子的产生。目的2.通过干扰IKBA、p38MAPK和TGF-B-Smad信号通路，探讨肺炎链球菌和NTHi协同激活核因子-kB和细胞因子的信号机制。目的3.通过干扰IkBA、p38和MEKK1信号通路，探讨肿瘤坏死因子-α和神经营养因子hi协同激活核因子-kB和细胞因子的信号机制。意义：研究多种致病因素联合调节核因子-kB的信号机制，不仅将对炎症在OM发病机制中的调控有新的认识，而且将为抑制OM患者的炎症反应开辟新的治疗靶点。

DESCRIPTION (provided by applicant): Streptococcus pneumoniae (S. pneumoniae) and nontypeable Haemophilus influenzae (NTHi) are the major human pathogens causing otitis media (OM). Inflammation is the hallmark of OM. However, the molecular mechanisms underlying inflammation in OM remain poorly defined. Our long-term objective is to understand how the inflammatory responses are induced and regulated in the pathogenesis of OM. Given the fact that, in in vivo situations, multiple factors are existing simultaneously and up to 24-48% of OM patients have combined infections with S. pneumoniae and NTHi, we hypothesize that NF-kB is synergistically regulated by multiple pathogenic inducers via activation of multiple signaling pathways in the pathogenesis of OM (overall hypothesis). Indeed, our preliminary results indicate that NTHi and S. pneumoniae or NTHi and TNF-alfa synergistically activate NF-kB and cytokine production via multiple signaling pathways involving IKBcz, p38 MAPK and MEKK1. Thus, these encouraging results have laid a solid foundation for further investigation of the signaling mechanisms underlying NF-kB activation and cytokine production by multiple pathogenic inducers (short-term objective). Aim 1. Determine whether and how activation of TGF- beta-Smad signaling pathway is required for NTHi-induced NF-kB activation and cytokine production by perturbing their signaling. Aim 2. Determine the signaling mechanisms underlying the synergistic activation of NF-KB and cytokine induction by S. pneumoniae and NTHi by perturbing IKBa, p38 MAPK and TGF-B-Smad signaling. Aim 3. Determine the signaling mechanisms underlying the synergistic activation of NF-kB and cytokine induction by TNF-a and NTHi by perturbing IkBa, p 38 and MEKK1 signaling. Significance: Investigating the signaling mechanisms underlying the combinatorial regulation of NF-kB by multiple pathogenic factors will not only bring new insights into the regulation of inflammation in the pathogenesis of OM, but also open up novel therapeutic targets for inhibiting inflammatory responses in patients with OM.