Effect/alveolar beta2 adrenergic receptor overexpression

描述（由申请人提供）：肺水肿从 肺泡作为一个积极的运输Na+的结果，从空气中， 肺泡上皮转运蛋白。据观察，在某些类型中， 这些主动清除机制受损。因此，在本发明中， 改善肺泡主动转运的方法可能被证明对 治疗这种常见病。 据报道，β 2-肾上腺素能激动剂增加活性Na约 通过β 2-肾上腺素能受体的转运和肺泡液体清除（ALC） （β 2 AR）和长期使用f3-激动剂降低β 2 AR表达 在肺泡上皮中。在本提案中包含的初步数据中， 已经观察到药理学剂量的β 2-激动剂使肺泡 f β 2 AR和肺泡β 2 AR过度表达增加ALC。这些 研究使我们假设：1）肺泡f32 AR受 激动剂诱导的功能丧失（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这些过程来积极影响这些过程。 受体脱敏模式和增加功能性 细胞膜上的受体。 为了验证这些假设，我们提出了三个相互关联的具体目标 将分子技术与生理学研究相结合， 深入了解肺泡β 2 AR的作用和调节： 具体目标#1：确定肺泡β 2 AR过表达是否可以改善 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的脱敏约激动剂，如果脱敏 影响ALC，并且如果过度表达则减弱受体脱敏。 具体目标#3：检测实验模型中β 2 AR功能是否受损 肺损伤和if受体功能可以通过在 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 年造成大量的发病率和死亡率。目前没有 针对这种危及生命的疾病的特殊治疗。这个目标 建议是提高我们对肺泡之间相互作用的理解， β 2 AR与肺泡Na、K-ATP酶、Na ~+通道和ALC的关系。的 本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，并开发新的治疗方法，以改善肺泡β 2 AR 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.