BETA-ADRENERGIC GENE TRANSFER AND PULMONARY FUNCTION

描述 通过β/2-肾上腺素能受体(AR)传递信号是至关重要的 对两者肺血管的正常调节很重要 呼吸道和动脉。β/2ARs在肺平滑肌中的激活 会导致放松和扩张。β/2/ARs在肺损伤中的作用 疾病过程还不是很清楚，但出现了BetaAR信号 在几种类型的肺细胞中很重要。如此广泛的参与 基础肺生理学中的β/2AR确实提示了β/2AR的作用 在包括反应性呼吸道疾病在内的多种疾病中发出信号， 阻塞性肺疾病和肺动脉高压。引言 将外来DNA注入体内完整器官的体细胞中最近 已经被证明是可行的。呼吸道和血管系统的可达性 肺部喜欢这个器官，它是基因治疗的重要靶点 研究可能导致特定的基因治疗策略来缓解 具有呼吸道阻力增加成分的肺部疾病 和血管平滑肌。本提案的制定是为了了解 β-AR信号可在成人肺和肺中增强 外源腺病毒转导β/2ARs后的血管形成 一种β/2AR脱敏的多肽抑制剂。这两个转基因基因 已被证明在体内增加了β-AR信号。增加BetaAR 通过基因操作在肺中的信号特性代表 体内新增加的BetaAR信号。增加BetaAR信号 通过基因操作获得的特性代表了一种新颖的 增加体内的BetaAR信号。增加BetaAR信令属性 通过基因操作在肺中代表了一种新的治疗方法 改善松弛肺平滑肌的途径。因此， 这一提议的中心假设是DNA的基因转移 编码特定的BetaAR信号组件到肺将改变 肺功能。我们将使用兔子模型来完善条件 这些β/2AR重组腺病毒转基因的体内基因传递和检测 它们对肺功能的特殊影响。我们将使用兔子模型 为体内基因传递这些β/2AR创造更好的条件 腺病毒转基因并检测其对小鼠肺组织的特异性作用 生化信号转导及其在体内的生理后果 对呼吸道和血管平滑肌功能的影响。

DESCRIPTION Signaling through beta/2-adrenergic receptors (ARs) is critically important for the normal regulatory of pulmonary smooth muscle in both airways and arteries. Activation of beta/2ARs in pulmonary smooth muscle leads to relaxation and dilatation. The role of beta/2/ARs in pulmonary disease processes are not well understood but betaAR signaling appears important in several types of lung cells. Such widespread involvement of beta/2ARs in basic pulmonary physiology does suggest a role for beta/2AR signaling in a multitude of disorders including reactive airway disease, obstructive pulmonary disease and pulmonary hypertension. The introduction of foreign DNA into somatic cells of intact organs in vivo has recently been shown to be feasible. The accessibility of airways and vasculature of the lungs likes this organ an important target for gene therapy where research may lead to specific genetic therapeutic strategies to alleviate pulmonary diseases which have components of increased resistance of airway and vascular smooth muscle. This proposal is formulated to learn whether increased betaAR signaling can occur in the adult lung and pulmonary vasculature after exogenous adenoviral transgene delivery of beta/2ARs and a peptide inhibitor of beta/2AR desensitization. These two transgenes have been shown to increase in vivo betaAR signaling. Increasing betaAR signaling properties in the lung through genetic manipulation represents a novel increase in vivo betaAR signaling. Increasing betaAR signaling properties in the ling through genetic manipulation represents a novel increase in vivo betaAR signaling. Increasing betaAR signaling properties in the lung through genetic manipulation represents a novel therapeutic approach for improving relaxation pulmonary smooth muscle. Thus, the Central Hypothesis of this proposal is that gene transfer of DNA's encoding specific betaAR signaling components to the lung will alter pulmonary function. We will use a rabbit model to perfect conditions for in vivo gene delivery of these beta/2AR adenoviral transgenes and test their specific effects on pulmonary function. We will use a rabbit model to perfect conditions for in vivo gene delivery of these beta/2AR adenoviral transgenes and test their specific effects on pulmonary biochemical signal transduction and the in vivo physiological consequences on both airway and vascular smooth muscle function.