Structure-Function of Entamoeba Alcohol Dehydrogenase 2

无法分型的流感嗜血杆菌（NTHi）可导致慢性阻塞性肺病（COPD）和中耳炎（OM）感染。 两者都以炎症为特征。 NTHi诱导的炎症的分子机制仍然不清楚。 我们的长期目标是了解NTHi感染中诱导和调节炎症反应的分子机制。 我们最近的研究表明，NTHi通过Toll样受体2（TLR 2）（一种新鉴定的细菌受体）强烈激活核因子-κ B（NF-κ B）。 由于TLR 2在气道上皮细胞中的表达较低，并且TLR 2的过表达极大地增强了NTHi诱导的NF-κ B活化，因此我们假设NTHi通过特定的信号网络上调TLR 2。 我们的初步结果确实表明NTHi通过正NF-κ B途径和负p38 MAPK途径强烈上调TLR 2。 此外，糖皮质激素协同增强NTHi诱导的TLR 2上调。 这些令人鼓舞的结果为进一步研究NTHi诱导的TLR 2上调的分子机制（短期目标）奠定了坚实的基础。目标1.通过干扰NF-κ B信号传导途径确定NF-κ B活化对NTHi诱导的TLR 2上调的贡献。目标2.通过干扰p38信号通路确定p38 MAPK信号通路对NTHi诱导的TLR 2上调的贡献。目标3。通过研究糖皮质激素对NTHi诱导的p38通路活化的作用，确定糖皮质激素协同增强NTHi诱导的TLR 2上调的信号传导机制。重要性：了解NTHi诱导的TLR 2上调的信号传导机制不仅将为炎症的调节带来新的见解，而且还将为调节COPD和OM中的炎症反应开辟新的治疗靶点。 此外，阐明糖皮质激素增强NTHi诱导的TLR 2上调的分子机制将提供关于如何在临床中更适当地使用糖皮质激素的指导性信息。

Nontypeable Haemophilus influenzae (NTHi) causes infections in chronic obstructive pulmonary disease (COPD) and otitis media (OM). Both are characterized by inflammation. The molecular mechanisms underlying NTHi-induced inflammation remain poorly defined. Our long-term objective is to understand the molecular mechanisms by which the inflammatory response is induced and regulated in NTHi infections. Our recent studies showed that NTHi strongly activates nuclear factor-kappaB (NF- kappaB) via Toll-like Receptor 2 (TLR2), a newly identified receptor for bacteria. Because TLR2 expression in airway epithelial cells is low and overexpression of TLR2 greatly enhances NTHi-induced NF-kappaB activation, we hypothesize that NTHi up-regulates TLR2 via a specific signaling network. Our preliminary results indeed indicate that NTHi strongly up- regulates TLR2 via a positive NF-kappaB pathway and a negative p38 MAPK pathway. Moreover, glucocorticoids synergistically- enhance NTHi-induced TLR2 up-regulation. These encouraging results have thus laid a solid foundation for further investigation of the molecular mechanisms underlying NTHi-induced TLR2 up-regulation (short-term objective). Aim 1. Determine the contribution of NF-kappaB activation to NTHi-induced TLR2 up- regulation by perturbing NF-kappaB signaling pathways. Aim 2. Determine the contribution of p38 MAPK signaling pathway to NTHi- induced TLR2 up-regulation by perturbing p38 signaling pathway. Aim 3. Determine the signaling mechanisms by which glucocorticoids synergistically enhance NTHi-induced TLR2 up- regulation by studying the effect of glucocorticoids on NTHi- induced activation of p38 pathway. Significance: Understanding the signaling mechanisms underlying NTHi-induced TLR2 up- regulation will not only bring new insights into the regulation of inflammation, but will also open up novel therapeutic targets for modulating inflammatory responses in COPD and OM. Moreover, elucidating the molecular mechanisms by which glucocorticoids enhance NTHi-induced TLR2 up-regulation will provide instructive information regarding how to use glucocorticoids more appropriately in the clinic.