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

该子项目是利用NIH/NCRR资助的中心赠款提供的资源的许多研究子项目之一。子项目和研究者（PI）可能从另一个NIH来源获得主要资金，因此可以在其他CRISP条目中表示。所列机构为中心，不一定是研究者所在机构。哮喘是一种呼吸道慢性炎症性疾病，约占总人口的7%。嗜酸性粒细胞（EOS）被认为是主要的效应细胞，延长潜在的气道炎症成分病理分类为慢性脱皮嗜酸性支气管炎。虽然目前的疗法对一些患者有效，但仍需要开发新的治疗方法。这些拟议研究的重点是确定目标过程，这些过程可能被开发为基于EOS特异性机制的治疗方法，旨在中断EOS介导的事件。炎症消退机制将保持完整，并将避免永久性组织损伤/破坏。建议假设？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/炎症部位指导多种促炎事件。气道上皮来源的嗜酸性粒细胞趋化因子是开发基于机制的反义寡核苷酸治疗的重要靶点，该反义寡核苷酸治疗旨在中断过敏性和炎症性疾病中嗜酸性粒细胞介导的潜在慢性炎症。分子生物学和成像设施流式细胞术、荧光/共聚焦显微镜和凝胶记录仪器将用于根据以下特定目的来检验所提出的假设：特定目的1探索调节气道上皮细胞（AEC）中嗜酸性粒细胞趋化因子（CCL 11）、嗜酸性粒细胞趋化因子-2（CCL 24）和嗜酸性粒细胞趋化因子-3（CCL 26）的合成和释放的抗炎或促炎信号;具体目的2 <$探索CCL 11、CCL 24和CCL 26对AEC eotaxin CCR 3趋化因子受体的自分泌调节;具体目的3 <$研究CCL 11、CCL 24和CCL 26反义ODN在AEC中的摄取、细胞毒性和功能。这些研究的成功完成将进一步了解调节EOS粘附，引发/激活和延迟程序性细胞死亡的特定信号分子。这些信号的减少/激活可改善嗜酸性粒细胞诱导的炎性组织损伤并促进消退。

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.