Combinational regulation of inflammation in otitis media

描述（由申请人提供）：肺炎链球菌（S. pneumoniae）和不可分型的流感嗜血杆菌（NTHi）是引起中耳炎（OM）的主要人类病原体。炎症是OM的标志。然而，OM炎症的分子机制仍不明确。我们的长期目标是了解炎症反应是如何在OM的发病机制中被诱导和调节的。鉴于在体内情况下，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NF-kB在OM发病过程中通过激活多种信号通路，受到多种致病诱导因子的协同调节（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IKBcz、p38 MAPK和MEKK1等多种信号通路协同激活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剂激活NF-kB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TGF- β - smad信号通路的信号传导，确定nthi诱导的NF-kB激活和细胞因子产生是否需要TGF- β - smad信号通路的激活以及如何激活。目标2。通过干扰IKBa、p38 MAPK和TGF-B-Smad信号，确定肺炎链球菌和NTHi协同激活NF-KB和细胞因子诱导的信号传导机制。目标3。通过干扰IkBa、p38和MEKK1信号，确定TNF-a和NTHi协同激活NF-kB和细胞因子诱导的信号传导机制。意义：研究多种致病因子联合调控NF-kB的信号机制，不仅可以为OM发病过程中炎症的调控提供新的认识，还可以为OM患者抑制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.