Alpha1-Adrenoceptor Subtypes & Role in Pathophysiology

描述(申请人提供)：这是一个项目05-9年的申请，旨在加深我们对由α1-肾上腺素能受体(AR)亚型介导的信号转导和生理的分子和生化机制的了解。α1受体(A1a、A1B和a1D)是G蛋白偶联受体家族的成员，通过结合内源性儿茶酚胺、肾上腺素和去甲肾上腺素来调节交感神经系统。这些受体是目前治疗高血压、良性前列腺肥大和尿失禁的治疗靶点，通过它们在平滑肌收缩中的作用。信号通路和/或受体本身的改变可能与这些疾病的发病机制有关。因此，对这些受体的结构和功能及其信号转导机制的详细了解对于我们理解这些疾病的发病机制和治疗将是至关重要的。由于缺乏具有足够选择性的特异性抗体、激动剂和拮抗剂来防止亚型之间的交叉结合，目前对α1-AR亚型药理学(即定位、信号差异和病理学)的了解受到损害。在过去的资助中，我们的实验室通过表征结合口袋中有助于激动剂和拮抗剂结合以及亚型选择性的决定因素，在α1-AR亚型的结构和功能方面做出了重大贡献。我们还开发了系统过度表达Alpha1B-AR亚型的转基因小鼠，并表明它会导致神经和心血管病理。在本供资期间取得了重大进展，本申请是在这些意见的基础上提出的。基于这些结果，我们现在建议确定alpha1-AR亚型控制其功能的各个方面的相似或不同之处。这一应用将分子和细胞方法与最先进的体外和体内方法结合在一起，进行了一项全面的实验设计，这将显著增加我们对亚型特异性结合口袋、α1亚型之间的定位、信号和功能差异的理解，从而增强我们对药物设计和治疗策略的知识。

DESCRIPTION (provided by applicant): This is a request for years 05-9 of a project designed to further our understanding of the molecular and biochemical mechanisms of signal transduction and physiology mediated by alpha1-adrenergic receptor (AR) subtypes. Alpha1-ARs (a1A, a1B and a1D) are members of the G-protein-coupled receptor family of proteins that mediate the sympathetic nervous system by binding the endogenous catecholamines, epinephrine and norepinephrine. These receptors are a current therapeutic target in the management of hypertension, benign prostatic hypertrophy, and urinary incontinence through their role in smooth muscle contraction. Alterations in the signaling pathways and/or receptors themselves may contribute to the pathogenesis of these diseases. Thus, a detailed understanding of the structure-function of these receptors and their signal transduction mechanisms will be crucial to our understanding of the pathology and treatment of these diseases. The current state of knowledge in alpha1-AR subtype pharmacology (i.e. localization, signaling differences and pathology) are impaired due to the lack of specific antibodies, agonists and antagonists that have enough selectivity to prevent cross-binding among the subtypes. In past grants, our laboratory has made significant contributions to the structure-function of alpha1-AR subtypes by characterizing determinants in the binding pocket that contribute to agonist and antagonist binding and to subtype selectivity. We have also developed transgenic mice that systemically overexpress the alpha1B-AR subtype and showed that it causes neurological as well as cardiovascular pathology. Significant progress has been made in the current funding period and this application builds upon these observations. Based on these results, we now propose to determine how similar or different the alpha1-AR subtypes control various aspects of their function. This application integrates molecular and cellular methodologies with state of the art in vitro and in vivo approaches in an comprehensive experimental design that will significantly increase our understanding of the subtype-specific binding pocket, the localization, signaling and functional differences between alpha1-subtypes that will enhance our knowledge of drug design and therapeutic strategies.