BETA2-ADRENERGIC RECEPTOR DOWN-REGULATION IN ASTHMA

哮喘中的β2-肾上腺素受体下调

• 批准号: 6532638
• 负责人: Stacie M Jones
• 金额: $ 12.66万
• 依托单位: UNIV OF ARKANSAS FOR MED SCIS
• 依托单位国家: 美国
• 财政年份: 2000
• 资助国家: 美国
• 起止时间: 2000-08-01 至 2003-04-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6532638
• 关键词: asthma; beta adrenergic receptor; beta antiadrenergic agent; clinical research; genetic polymorphism; human subject; receptor expression; respiratory disorder chemotherapy; respiratory pharmacology

Dr. Stacie Jones, the PI, is an assistant professor who completed her pediatric allergy/immunology fellowship in 1994. In this proposal, she outlines a program to study the effects of prolonged beta-agonist treatment on beta2 adrenergic receptor (beta2AR) regulation in patients with asthma. Development of tolerance to beta-agonists has been a significant concern in the treatment of asthma-related bronchospasm. Both in vitro and in vivo studies have demonstrated change in beta2AR density in relation to prolonged beta-agonist exposure. Trafficking of beta2AR to lysosomes for degradation describes the process of down-regulation. Despite its importance in determining responsiveness to beta-agonists, little is known about the molecular mechanisms driving beta2AR down-regulation. This project proposes to use a novel approach employing beta2AR- apidermal growth factor receptor chimeras to define the important molecular determinants and intracellular protein interactions that are responsible for lysosomal sorting and beta2AR down- regulation following prolonged beta-agonist exposure. Information gained in the laboratory will be applied in translational research at the bedside to correlate-the cellular mechanisms responsible for beta2AR down-regulation with genetic polymorphisms of the beta2AR in asthmatics. The central hypothesis of this proposal is that beta2AR down-regulation is driven by specific interaction between a soluble intracellular protein with a beta2AR lysosomal targeting domain and that the rate of down-regulation is modified by polymorphisms in the amino-terminal region of the beta2AR. Employing a series of molecular and cellular biology techniques, the hypothesis will be tested via the following Specific Aims: 1) Identify the functional beta2AR lysosomal targeting domain driving beta2AR trafficking and define the impact of beta2AR amino-terminus polymorphisms on beta2AR down-regulation, 2) Determine the intracellular lysosomal targeting protein(s) responsible for beta2AR sorting to lysosomes, and 3) Assess the clinical relevance of beta2AR polymorphisms in receptor trafficking and down-regulation in asthmatics in the setting of prolonged agonist exposure. Information gained from the proposed studies will advance our knowledge of the association between beta-agonist exposure and beta2AR down-regulation and may led to new approaches in asthma therapeutics. The PI will take advantage of the strong mentoring, protected research time and the outstanding academic resources of the University of Arkansas for Medical Sciences to reach her goal of becoming an independent investigator.

PI Stacie Jones博士是一位助理教授，在1994年完成了儿科过敏/免疫学研究金。在此提案中，她概述了一项计划，概述了一项计划，旨在研究β2型阳性治疗对β2肾上腺素能受体（beta2ar）调节的延长影响。 对β-激动剂的耐受性的发展一直是治疗与哮喘相关的支气管痉挛的重要关注点。 体外和体内研究都表明，β2AR密度与长时间的β-激动剂暴露有关。 将β2AR贩运到溶酶体降解，描述了下调的过程。 尽管它在确定对β激动剂的反应性方面的重要性，但对驱动β2AR下调的分子机制知之甚少。 该项目建议采用一种新的方法，该方法采用β2AR-APIDERMAL生长因子受体嵌合体来定义重要的分子决定因素和细胞内蛋白质相互作用，这些相互作用是造成溶酶体分类和β2AR调节后延长的β-激动暴露后负责的。实验室中获得的信息将应用于床边的转化研究中，以将负责β2AR下调的细胞机制与哮喘患者中β2AR的遗传多态性相关联。 该提议的中心假设是，β2AR下调是由可溶性细胞内蛋白与β2AR溶酶体靶向结构域之间的特异性相互作用驱动的，并且下调速率是由Beta2ar氨基末端区域的多态性改变的。 采用一系列分子和细胞生物学技术，将通过以下特定目的对假设进行检验：1）确定功能性beta2ar溶酶体靶向靶向驱动β2AR运输的靶向结构域，并定义β2AR氨基 - 氨基末端多态性对beta2ar potition的影响，确定beta2ar pottain intakelly in Interaimal in Interaimal in Interain for in Intainbar in Intainbar in Intainimal for in Intainbariunl a inspariuntar in actaimalull 2）对溶酶体进行分类，3）评估β2AR多态性在受体运输和哮喘患者下调的临床相关性。 从拟议的研究中获得的信息将提高我们对β激动剂暴露与β2AR下调之间关联的了解，并可能导致哮喘治疗方法的新方法。 PI将利用强大的指导，受保护的研究时间以及阿肯色大学医学科学的杰出学术资源，以实现成为独立研究者的目标。