5 OXOETE AND MECHANISMS OF EOSINOPHIL ALLERGIC RESPONSES

描述（根据申请人的摘要和具体目标改编）： 负责将嗜酸性粒细胞（Eo）募集到哮喘部位的药物， 其他疾病的定义仍然不明确。 趋化因子（CF）是 目前的嫌疑人。 然而，CF往往是相对较弱的Eo刺激， 对中性粒细胞（Neu）的效力更大，因此似乎更适合介导 Neu-based炎症反应而不是Eo-based过敏反应。 证据 表明一种新描述的类二十烷酸，5-oxoETE，具有极强的效力， 动力和选择性刺激Eo迁移。 它类似于古典 CF通过与百日咳相关的假定受体（Rs）发挥作用 毒素（PT）敏感的异源三聚体G蛋白（GPs）。 然而， 与已知的CF相比，不仅在强度和EO-选择性方面，而且在其 刺激非趋化反应的能力有限， 显然完全依赖PT敏感的GP。 其他CF依赖于两者 PT不敏感和PT敏感GP。 申请书假定， 5-oxoETE对Eo的促过敏作用范围有限;这些作用 通过专用的R进行;这些R链接到一个独特的，可识别的 GP的子集;这些GP调节相应的独特的， 细胞信号和反应的可识别子集。 具体目标是 1）定义5-oxoETE刺激选定反应的能力， Eo和Neu中与这些反应相关的信号; 2）证明 Eo、Neu和分化的HL-60细胞中的5-oxoETE-R和EP;和3） 推导特定GP调节的信号和功能反应 班

DESCRIPTION (Adapted from applicant's abstract and specific aims): The agents responsible for recruiting eosinophils (Eo) to sites of asthma and other diseases remain ill-defined. Chemotactic factors (CFs) are among the current suspects. However, CFs often are relatively weak Eo-stimuli, have greater potency on neutrophils (Neu), and thus seem better suited to mediate Neu-based inflammatory rather than Eo-based allergic reactions. Evidence indicates that a newly described eicosanoid, 5-oxoETE, has extreme potency, power, and selectivity in stimulating Eo migration. It resembles classical CFs in operating through presumptive receptors (Rs) that link to pertussis toxin (PT)-sensitive heterotrimeric G proteins (GPs). However, it differs from known CFs not only in strength and Eo-selectivity but also in its limited ability to stimulate non-chemotactic responses as well as its apparently complete reliance on PT-sensitive GPs. Other CFs rely on both PT-insensitive and PT-sensitive GPs. The application postulates that 5-oxoETE has a restricted range of proallergic actions on Eo; these actions proceed via dedicated Rs; these Rs link to a distinctive, identifiable subset of GPs; and these GPs regulate a correspondingly distinctive, identifiable subset of cell signals and responses. The specific aims are to: 1) Define 5-oxoETE's ability to stimulate selected responses and signals relevant to these responses in Eo and Neu; 2) Demonstrate 5-oxoETE-Rs and EPs in Eo, Neu, and differentiated HL-60 cells; and 3) Deduce the signals and functional responses regulated by specific GP classes.