PILOT STUDY--BAYLOR CHILD HEALTH RESEARCH CENTER

试点研究--贝勒儿童健康研究中心

• 批准号: 5212749
• 负责人: ROBERT H MOORE
• 金额: --
• 依托单位国家: 美国
• 资助国家: 美国
• 起止时间: 至
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/5212749
• 关键词: asthma; beta adrenergic receptor; beta antiadrenergic agent; cell membrane; cellular pathology; chemical kinetics; clone cells; gene expression; molecular pathology; pathologic process; protein kinase A; protein kinase C; receptor sensitivity; second messengers; suppressor mutations; transfection

The chronic use of beta2-adrenergic agonists may be associated with deterioration in asthma control and an increase in nonspecific bronchial responsiveness. This worsening in clinical status may be related to receptor desensitization after prolonged exposure to beta2-agonists. The beta2-adrenergic receptor (beta2AR) couples to its effector, adenylyl cyclase, via a signal transducing G/s protein. With agonist binding, there is a rapid uncoupling of receptor from G/s protein due to receptor phosphorylation. Within minutes, there is loss of membrane receptors due to endocytosis into early endosomes. With prolonged exposure to agonist, there is a loss of total cellular receptor (down-regulation), probably as a result of lysosomal degradation as well as decreased receptor synthesis. Studies of other receptors (for example, EGF-R) suggest that those destined for degradation in lysosomes travel from early endosomes to a separate late endosome compartment. The proposed studies will evaluate the intracellular route by which beta2AR are delivered to degradative organelles. Additionally, the mechanisms regulating this process will be determined, focusing on the roles of the small GTPase rab7, cellular protein kinases, and beta2AR mutations in this process. These studies will lead to an improved understanding of the down-regulation of beta2AR, opening the way for developing therapeutics based on regulating the cellular trafficking of these receptors.

长期使用β2-肾上腺素能激动剂可能与 哮喘控制恶化和非特异性支气管的增加 响应能力。 这种临床状况恶化可能与 长时间暴露于beta2激动剂后，受体脱敏。 这 beta2-肾上腺素能受体（beta2ar）伴侣的效应器adenylyl 通过信号转导G/S蛋白的循环酶。 具有激动剂结合， 由于受体，G/S蛋白的受体迅速解偶联 磷酸化。 几分钟之内，膜受体损失到期 将内吞作用成早期内体。 长时间暴露于激动剂， 总细胞受体损失（下调），可能是 溶酶体降解以及受体合成降低的结果。 对其他受体的研究（例如，EGF-R）表明 注定要在溶酶体中降解从早期内体传播到 单独的晚期内体隔室。 拟议的研究将评估 β2AR递送至降解的细胞内途径 细胞器。 此外，调节此过程的机制将是 确定，重点介绍小GTPase Rab7的作用，细胞 在此过程中，蛋白激酶和β2AR突变。 这些研究 将导致人们对beta2ar下调的下调有所改善， 开发基于调节的治疗剂的道路 这些受体的细胞运输。