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

本子项目是利用由NIH/NCRR资助的中心赠款提供的资源的众多研究子项目之一。子项目和研究者（PI）可能已经从另一个NIH来源获得了主要资金，因此可以在其他CRISP条目中表示。列出的机构是中心的，不一定是研究者的机构。哮喘是一种影响7%人口的不治之症，被定义为呼吸道的慢性炎症性疾病。嗜酸性粒细胞（EOS）被认为是延长潜在气道炎症成分的主要效应细胞，病理分类为慢性脱皮性嗜酸性支气管炎。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。炎症解决机制将保持完整，并避免永久性组织损伤/破坏。气道上皮是eotaxins的主要来源，eotaxins是一个嗜酸性细胞因子家族，在过敏/炎症部位指导多种促炎事件。气道上皮源性eotaxins是开发基于机制的反义寡核苷酸辅助疗法的重要靶点，旨在中断嗜酸性粒细胞介导的过敏性和炎症性疾病的潜在慢性炎症。分子生物学和成像设备流式细胞术，荧光/共聚焦显微镜和凝胶记录仪器将根据以下具体目的来验证所提出的假设：具体目的1：探索调节气道上皮细胞（AEC）中eotaxin (CCL11), eotaxin-2 （CCL24）和eotaxin-3 （CCL26）合成和释放的抗炎或促炎信号；目的2：探讨CCL11、CCL24、CCL26对AEC eotaxin CCR3趋化因子受体的自分泌调节作用；研究CCL11、CCL24和CCL26在AEC中的反义ODN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、启动/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/激活可能会改善嗜酸性粒细胞引起的炎症组织损伤并促进其消退。

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.