Combinational regulation of inflammation in otitis media

性状（由申请方提供）：肺炎链球菌（S.肺炎嗜血杆菌（Haemophilus pneumoniae）和不可分型的流感嗜血杆菌（Haemophilus influenzae，NTHi）是引起中耳炎（otitis media，OM）的主要人类病原体。炎症是OM的标志。然而，OM炎症的分子机制仍然不清楚。我们的长期目标是了解OM发病机制中炎症反应是如何诱导和调节的。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S.通过对肺炎链球菌和NTHi的研究，我们假设NF-kB在OM的发病机制中通过激活多种信号传导途径被多种致病诱导物协同调节（总体假设）。我们的初步结果表明，NTHi和S.肺炎链球菌或NTHi和TNF-α通过涉及IKBcz、p38 MAPK和MEKK 1的多种信号传导途径协同激活NF-κ B和细胞因子产生。因此，这些令人鼓舞的结果奠定了坚实的基础，为进一步调查的信号转导机制的NF-κ B激活和细胞因子的生产由多种致病诱导剂（短期目标）。目标1.通过干扰TGF-β-Smad信号通路的信号传导，确定NTHi诱导的NF-κ B活化和细胞因子产生是否需要TGF-β-Smad信号通路的活化以及活化方式。目标2.确定S. p38 MAPK和TGF-B-Smad信号通路。目标3.通过干扰IkBa、p38和MEKK 1信号传导，确定TNF-α和NTHi协同激活NF-κ B和细胞因子诱导的信号传导机制。重要性：研究多种致病因子联合调控NF-κ B的信号转导机制不仅可以为OM发病机制中的炎症调节提供新的见解，还可以为OM患者的炎症反应抑制开辟新的治疗靶点。

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.