Effect/alveolar beta2 adrenergic receptor overexpression

效应/肺泡β2肾上腺素受体过度表达

• 批准号: 6754524
• 负责人: Phillip H Factor
• 金额: $ 28.49万
• 依托单位: COLUMBIA UNIVERSITY HEALTH SCIENCES
• 依托单位国家: 美国
• 财政年份: 2001
• 资助国家: 美国
• 起止时间: 2001-07-01 至 2005-05-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6754524
• 关键词: active transport; beta adrenergic receptor; beta antiadrenergic agent; disease /disorder model; gene therapy; laboratory rat; lung injury; membrane permeability; nonhuman therapy evaluation; pulmonary edema; receptor sensitivity; respiratory airway clearance; respiratory epithelium; sodium channel; sodium potassium exchanging ATPase; transfection

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.

描述（由申请人提供）：从 肺泡是由于Na+从空域中主动运输的结果 肺泡上皮转运蛋白。已经观察到某些类型 这些主动清除机制的肺水肿受损。因此， 改善肺泡活性转运的方法可能对 治疗这种常见状况。 据报道，β2-肾上腺素能激动剂增加了主动Na 通过beta2-肾上腺素能受体的运输和肺泡液体清除（ALC） （beta2 ar），长时间使用F3激动剂会降低beta2ar的表达 在牙槽上皮。在本提案中包含的初步数据中我们 已经观察到beta2激动剂脱敏肺泡的药理​​剂量 F beta2ar和肺泡β2AR超过表达会增加ALC。这些 研究导致我们假设：1）肺泡F32AR受 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型肺泡溶质转运，3）和 表达的受体可以通过改变来积极影响这些过程 受体脱敏模式并增加功能的数量 细胞膜中的受体。 为了检验这些假设，我们提出了三个相关的特定目的 将分子技术与生理研究整合在一起，以生成新的 对肺泡β2AR的作用和调节的见解： 特定目的＃1：确定肺泡beta2ar超过表达能否改善 受体功能和儿茶酚胺反应性ALC。特定目标＃2：测试是否 如果脱敏 影响ALC，如果过度表达会减弱受体脱敏。 特定目标＃3：测试实验模型中beta2ar函数是否受损 肺损伤和是否可以通过过度表达提高受体功能 急性肺损伤的模型。 心脏病和非心脏病性肺水肿影响数百万 一年导致大量发病率和死亡率。目前没有 对这种威胁生命的条件的特定治疗方法。目标的目标 建议是提高我们对肺泡之间相互作用的理解 beta2ar和肺泡Na，K-atpases，Na关于通道和ALC。这 该提案中包含的实验计划已结构结构，以使我们能够 测试我们的假设并开发新的疗法以改善肺泡beta2ar 功能和肺水肿清除。