Effect/alveolar beta2 adrenergic receptor overexpression

描述（由申请人提供）： 肺水肿已从体内清除 肺泡是钠从空气空间主动运输出来的结果 肺泡上皮转运蛋白。据观察，在某些类型中 肺水肿时，这些主动清除机制受到损害。因此， 改善肺泡主动运输的方法可能对 治疗这种常见病症。 据报道，β2-肾上腺素能激动剂可增加活性Na 通过 β2 肾上腺素能受体进行运输和肺泡液体清除 (ALC) (beta2 AR) 并且长期使用 f3 激动剂会降低 beta2AR 表达 在肺泡上皮中。在本提案中包含的初步数据中，我们 观察到药理学剂量的 β2 激动剂可使肺泡脱敏 f beta2AR 和肺泡 beta2AR 过度表达会增加 ALC。这些 研究使我们假设：1) 肺泡 f32AR 受到 激动剂引起的功能丧失（脱敏），2) 受体丧失 功能减弱儿茶酚胺反应性肺泡溶质转运，3) 和 受体过度表达可以通过改变来积极影响这些过程 受体脱敏模式和增加功能性受体的数量 细胞膜上的受体。 为了检验这些假设，我们提出了三个相互关联的具体目标 将分子技术与生理研究相结合以产生新的 关于肺泡 beta2AR 的作用和调节的见解： 具体目标#1：确定肺泡 beta2AR 过度表达是否可以改善 受体功能和儿茶酚胺反应性 ALC。具体目标#2：测试是否 肺泡β AR 被大约激动剂脱敏，如果脱敏 影响 ALC，如果过度表达会减弱受体脱敏。 具体目标#3：测试实验模型中 beta2AR 功能是否受损 肺损伤以及受体功能是否可以通过过度表达来改善 急性肺损伤模型。 心源性和非心源性肺水肿分别影响数百万人 年造成大量发病率和死亡率。目前不存在 针对这种危及生命的病症的特定治疗。此举的目标 建议是为了提高我们对肺泡之间相互作用的理解 beta2AR 和肺泡 Na、K-ATP 酶、Na 通道和 ALC。的 该提案中包含的实验计划的结构使我们能够 测试我们的假设并开发新的疗法来改善肺泡 beta2AR 功能和肺水肿清除。

DESCRIPTION (provided by applicant): Pulmonary edema is cleared from the alveolus as a result of the active transport of Na+ out from the airspace by alveolar epithelial transport proteins. It has been observed that in some types of pulmonary edema these active clearance mechanisms are impaired. Thus, methods that improve alveolar active transport may prove useful for the treatment of this common condition. It has been reported that beta2-adrenergic agonists increase active Na about transport and alveolar liquid clearance (ALC) via beta2-Adrenergic Receptors (beta2 AR) and that prolonged use of f3-agonists decreases beta2AR expression in the alveolar epithelium. In preliminary data included in this proposal we have observed that pharmacologic doses of a beta2-agonist desensitize alveolar f beta2ARs and that alveolar beta2AR over expression increases ALC. These studies caused us to hypothesize that: 1) alveolar f32ARs are subject to agonist-induced loss of function (desensitization), 2) loss of receptor function attenuates catecholamine responsive alveolar solute transport, 3) and receptor over expression can positively affect these processes by altering receptor desensitization patterns and increasing the number of functional receptors in the cell membrane. To test these hypotheses we are proposing three inter related specific aims that integrate molecular techniques with physiologic studies to generate new insights into the role and regulation of alveolar beta2ARs: Specific Aim #1: To determine if alveolar beta2AR over expression can improve receptor function and catecholamine responsive ALC. Specific Aim #2: To test if alveolar beta AR's are desensitized by about agonists, if desensitization affects ALC, and if over expression attenuates receptor desensitization. Specific Aim #3: To test if beta2AR function is impaired in experimental models of lung injury and if receptor function can be improved via over expression in models of acute Lung injury. Cardiogenic and non-cardiogenic pulmonary edema affect millions of people each year causing substantial morbidity and mortality. Currently there exists no specific treatment for this life-threatening condition. The goal of this proposal is to improve our understanding of the interactions between alveolar beta2ARs and alveolar Na, K-ATPases, Na about channels and ALC. The experimental plan included in this proposal has been structured to allow us to test our hypotheses and develop novel therapies to improve alveolar beta2AR function and pulmonary edema clearance.