Structure-Function of Entamoeba Alcohol Dehydrogenase 2

不可分型流感嗜血杆菌（NTHi）引起慢性阻塞性肺疾病（COPD）和中耳炎（OM）感染。两者都以炎症为特征。nthi诱导炎症的分子机制仍不明确。我们的长期目标是了解NTHi感染中炎症反应被诱导和调节的分子机制。我们最近的研究表明，NTHi通过toll样受体2 （TLR2）强烈激活核因子- κ b (NF- κ b)， TLR2是一种新发现的细菌受体。由于TLR2在气道上皮细胞中的表达较低，而TLR2的过表达大大增强了NTHi诱导的NF-kappaB激活，我们假设NTHi通过特定的信号网络上调TLR2。我们的初步结果确实表明，NTHi通过NF-kappaB阳性通路和p38 MAPK负通路强烈上调TLR2。此外，糖皮质激素协同增强nthi诱导的TLR2上调。这些令人鼓舞的结果为进一步研究nthi诱导的TLR2上调的分子机制奠定了坚实的基础（短期目标）。目的1。通过干扰NF-kappaB信号通路，确定NF-kappaB激活对nthi诱导的TLR2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TLR2上调的贡献。目标3。通过研究糖皮质激素对NTHi诱导的p38通路激活的影响，确定糖皮质激素协同增强NTHi诱导的TLR2上调的信号机制。意义：了解nthi诱导的TLR2上调的信号机制，不仅可以为炎症调节提供新的见解，而且还可以为调节COPD和OM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TLR2上调的分子机制将为如何在临床中更恰当地使用糖皮质激素提供指导性信息。

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.