Alpha1-Adrenoceptor Subtypes & Role in Pathophysiology

Alpha1-肾上腺素受体亚型

基本信息

  • 批准号:
    6893299
  • 负责人:
  • 金额:
    $ 47.37万
  • 依托单位:
  • 依托单位国家:
    美国
  • 项目类别:
  • 财政年份:
    1999
  • 资助国家:
    美国
  • 起止时间:
    1999-07-15 至 2007-06-30
  • 项目状态:
    已结题

项目摘要

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.
描述(由申请人提供):这是一个05-9年的项目申请,旨在进一步了解α - 1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。Alpha1-ARs (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介导交感神经系统。这些受体通过其在平滑肌收缩中的作用,是目前治疗高血压、良性前列腺肥大和尿失禁的治疗靶点。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,详细了解这些受体的结构功能及其信号转导机制将对我们理解这些疾病的病理和治疗至关重要。由于缺乏特异性抗体、激动剂和拮抗剂,这些特异性抗体、激动剂和拮抗剂具有足够的选择性来防止亚型之间的交叉结合,目前对alpha1-AR亚型药理学(即定位、信号传导差异和病理)的了解状况受到损害。在过去的资助中,我们的实验室通过表征结合口袋中的决定因素,对α - 1- ar亚型的结构-功能做出了重大贡献,这些决定因素有助于激动剂和拮抗剂的结合以及亚型选择性。我们还开发了系统性过表达alpha1B-AR亚型的转基因小鼠,并表明它引起神经系统和心血管病理。在目前的供资期间取得了重大进展,这项应用建立在这些观察的基础上。基于这些结果,我们现在建议确定α 1- ar亚型如何相似或不同地控制其功能的各个方面。该应用程序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,进行全面的实验设计,这将大大增加我们对亚型特异性结合袋、α 1亚型之间的定位、信号传导和功能差异的理解,从而增强我们对药物设计和治疗策略的了解。

项目成果

期刊论文数量(0)
专著数量(0)
科研奖励数量(0)
会议论文数量(0)
专利数量(0)

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DIANNE M PEREZ其他文献

DIANNE M PEREZ的其他文献

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{{ truncateString('DIANNE M PEREZ', 18)}}的其他基金

Early Stage Studies of a Novel Positive Allosteric Modulator of the Alpha1-Adrenergic Receptor to Treat Alzheimer's Disease
新型α1-肾上腺素受体正变构调节剂治疗阿尔茨海默病的早期研究
  • 批准号:
    10380631
  • 财政年份:
    2020
  • 资助金额:
    $ 47.37万
  • 项目类别:
Early Stage Studies of a Novel Positive Allosteric Modulator of the Alpha1-Adrenergic Receptor to Treat Alzheimer's Disease
新型α1-肾上腺素受体正变构调节剂治疗阿尔茨海默病的早期研究
  • 批准号:
    10153647
  • 财政年份:
    2020
  • 资助金额:
    $ 47.37万
  • 项目类别:
Early Stage Studies of a Novel Positive Allosteric Modulator of the Alpha1-Adrenergic Receptor to Treat Alzheimer's Disease
新型α1-肾上腺素受体正变构调节剂治疗阿尔茨海默病的早期研究
  • 批准号:
    10609481
  • 财政年份:
    2020
  • 资助金额:
    $ 47.37万
  • 项目类别:
Alpha1A-Adrenoceptors in Cognition
Alpha1A-肾上腺素受体在认知中的作用
  • 批准号:
    9052682
  • 财政年份:
    2015
  • 资助金额:
    $ 47.37万
  • 项目类别:
Protective signaling mechanisms of the alpha1A-adrenoceptor
α1A-肾上腺素受体的保护性信号传导机制
  • 批准号:
    8109923
  • 财政年份:
    2010
  • 资助金额:
    $ 47.37万
  • 项目类别:
Protective signaling mechanisms of the alpha1A-adrenoceptor
α1A-肾上腺素受体的保护性信号传导机制
  • 批准号:
    7982876
  • 财政年份:
    2010
  • 资助金额:
    $ 47.37万
  • 项目类别:
Protective signaling mechanisms of the alpha1A-adrenoceptor
α1A-肾上腺素受体的保护性信号传导机制
  • 批准号:
    8257899
  • 财政年份:
    2010
  • 资助金额:
    $ 47.37万
  • 项目类别:
Protective signaling mechanisms of the alpha1A-adrenoceptor
α1A-肾上腺素受体的保护性信号传导机制
  • 批准号:
    8459522
  • 财政年份:
    2010
  • 资助金额:
    $ 47.37万
  • 项目类别:
Alpha1-Adrenoceptor Subtypes & Role in Pathophysiology
Alpha1-肾上腺素受体亚型
  • 批准号:
    6745100
  • 财政年份:
    1999
  • 资助金额:
    $ 47.37万
  • 项目类别:
ALPHA1 ADRENOCEPTOR SUBTYPES AND ROLE IN PATHOPHYSIOLOGY
ALPHA1 肾上腺素受体亚型及其在病理生理学中的作用
  • 批准号:
    2908627
  • 财政年份:
    1999
  • 资助金额:
    $ 47.37万
  • 项目类别:

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  • 批准号:
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