MBRA: SUBPROJECT 1 - AIRWAY EPITHELIAL CELLS AS TARGETS FOR ANTI-INFLAMMATORY

这个子项目是许多研究子项目中利用 资源由NIH/NCRR资助的中心拨款提供。子项目和 调查员(PI)可能从NIH的另一个来源获得了主要资金， 并因此可以在其他清晰的条目中表示。列出的机构是 该中心不一定是调查人员的机构。 影响7%人口的不治之症哮喘被定义为一种慢性呼吸道炎症性疾病。嗜酸性粒细胞(EOS)被认为是延长潜在的呼吸道炎症成分的主要效应细胞，病理上被归类为慢性脱屑性嗜酸性支气管炎。虽然目前的治疗方法对一些患者有效，但人们认为有必要开发新的治疗方法。这些拟议的调查的重点是确定目标过程，这些过程可能被开发为基于EOS特定机制的治疗方法，旨在中断EOS介导的事件。炎症消解机制将保持不变，永久性组织损伤/破坏将被绕过。建议假说：气道上皮是嗜酸性粒细胞趋化因子的主要来源，嗜酸性粒细胞选择性细胞因子家族在过敏/炎症部位引导多种促炎事件。呼吸道上皮源性嗜酸性粒细胞趋化因子是开发基于机制的反义寡核苷酸辅助治疗的重要靶点，旨在阻断嗜酸性粒细胞介导的变态反应性和炎症性疾病潜在的慢性炎症。我们将利用分子生物学和成像设备的流式细胞术、荧光/共聚焦显微镜和凝胶成像仪器，根据以下特定目的来验证提出的假说：特定目的1探索调节气道上皮细胞(AEC)合成和释放嗜酸性粒细胞趋化因子(CCL11)、嗜酸性粒细胞趋化因子-2(CCL24)和嗜酸性粒细胞趋化因子-3(CCL26)的抗炎或促炎信号；特异性目的2探讨CCL11、CCL24和CCL26对CCR3趋化因子受体中的嗜酸性粒细胞趋化因子的自分泌调节；以及特异性目的3？研究CCL11、CCL24和CCL26反义ODN的摄取、细胞毒性和功能。这些研究的成功完成将进一步了解调控EOS黏附、启动/激活和延缓细胞程序性死亡的特定信号分子。这些信号的减少/激活可能减轻嗜酸性粒细胞诱导的炎性组织损伤，促进其消退。

This subproject is one of many research subprojects utilizing the resources provided by a Center grant funded by NIH/NCRR. The subproject and investigator (PI) may have received primary funding from another NIH source, and thus could be represented in other CRISP entries. The institution listed is for the Center, which is not necessarily the institution for the investigator. Asthma, in incurable illness affecting 7% of the population, is defined as a chronic inflammatory disorder of the airways. Eosinophils (EOS) are considered the main effector cells that prolong the underlying airway inflammatory component pathologically classified as a chronic desquamating eosinophilic bronchitis. Though current therapies are effective for some patients, there is an identified need for development of new treatments. The focus of these proposed investigations is the identification of target processes that may be developed as EOS-specific mechanism-based therapeutics designed to interrupt EOS-mediated events. Inflammation resolving mechanisms would remain intact and permanent tissue damage/destruction would be circumvented. Proposal Hypothesis ¿ The airway epithelium is a major source of the eotaxins, a family of eosinophil-selective cytokines that direct multiple proinflammatory events at sites of allergy/inflammation. Airway epithelium-derived eotaxins are an important target for development of mechanism-based antisense oligonucleotide adjunctive therapies designed to interrupt the eosinophil-mediated underlying chronic inflammation in allergic and inflammatory disorders. Molecular Biology and Imaging facility flow cytometry, fluorescence/confocal microscopy and gel documentation instrumentation will be used to test the proposed hypothesis according to the following specific aims: specific aim 1 ¿ Explore the anti- or pro-inflammatory signals which modulate the synthesis and release of eotaxin (CCL11), eotaxin-2 (CCL24) and eotaxin-3 (CCL26) from airway epithelial cells (AEC); specific aim 2 ¿ Explore the autocrine regulation of CCL11, CCL24 and CCL26 on the AEC eotaxin CCR3 chemokine receptor; and specific aim 3 ¿ Investigate CCL11, CCL24 and CCL26 antisense ODN uptake, cytotoxicity and function in AEC. Successful completion of these investigations will further knowledge of the specific signaling molecules which regulate EOS adhesion, priming/activation, and delay of programmed cell death. Reduction/activation of these signals may ameliorate eosinophil-induced inflammatory tissue injury and promote resolution.