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Protective signaling mechanisms of the alpha1A-adrenoceptor

α1A-肾上腺素受体的保护性信号传导机制

基本信息

批准号：
8459522
负责人：
DIANNE M PEREZ
金额：
$ 36.99万
依托单位：
CLEVELAND CLINIC LERNER COM-CWRU
依托单位国家：
美国
项目类别：
财政年份：
2010
资助国家：
美国
起止时间：
2010-07-15 至 2015-04-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8459522
关键词：
ADRBK1 gene ADRBK2 gene Adrenergic Agonists Adrenergic Antagonists Adrenergic Receptor Affinity Animal Model Antihypertensive Agents Apoptosis Apoptotic Binding Blood Pressure Cardiac Cardiovascular Physiology Caspase Catecholamines Chronic Clinical Clinical Trials Coupling Cytokine Activation Data Development Drug abuse Functional disorder G-Protein-Coupled Receptors GRK Heart Heart failure Hypertrophy IL6 gene Imidazolines In Vitro Inflammation Injury Interleukin-6 Ischemia Laboratories Lead Light Lipids MAP Kinase Gene MAPK14 gene Mediating Mus Muscle Cells Myocardial Infarction Myocardial Ischemia Nerve Degeneration Pathway interactions Pharmaceutical Preparations Phosphorylation Positioning Attribute Prostatic Diseases Prostatic hypertrophy Protein Isoforms Proteins Proteomics Publishing RGS2 gene Receptor Signaling Regulation Regulation of Apoptosis Pathway Research Role STAT3 gene Signal Pathway Signal Transduction Sympathetic Nervous System Transgenic Mice Work carvedilol caspase-3 comparative effective therapy in vivo in vivo Model mortality novel novel therapeutics preconditioning prevent public health relevance receptor coupling scaffold

项目摘要

DESCRIPTION (provided by applicant): Our objective is to understand differential signal transduction paradigms by which a1 -adrenergic receptor (AR) subtypes mediate protection versus damage in the heart. a1-AR subtypes (a1A, a1B and a1D) are G protein-coupled receptors that mediate the sympathetic nervous system by binding catecholamines. However, little is known about specific subtype functions. Our research has suggested that a1-AR signaling pathways may contribute to either cardioprotection or damage. a1-AR antagonists were initially thought to be useful in treating heart failure due to sympathetic overload. However, in the Antihypertensive and Lipid-Lowering Treatment to Prevent Heart Attack Trial, the use of a non-selective a1-AR antagonist worsened heart failure and increased mortality. In contrast, carvedilol, an antagonist of a1- and ¿-ARs but with higher affinity for the a1B-AR subtype, provides an effective treatment for chronic heart failure, suggesting that subtype-specific signaling may contribute to these differential effects of a1-AR blockade. Because of the use of a1-AR antagonists in prostatic disease, its increasing potential for treating drug abuse and neurodegeneration, determining the role of a1-AR subtypes in the heart has very important clinical implications. Our laboratory had made unique transgenic mice of the a1-AR subtypes and demonstrated differential regulation of cardiovascular function. We have published that the a1A-AR but not the a1B-AR protected the heart from ischemic injury. Chronic a1B-AR stimulation resulted in heart dysfunction, and inflammation. We have determined unique pathways that are differentially regulated by the a1-AR subtypes, such as apoptosis, STAT3 activation, and cytokine secretion, which may explain how the a1-AR subtypes differentially control cardiac adaptation. Our research may lead to the development of new therapeutic strategies to treat heart failure and ischemia. This proposal focuses on a1-AR subtypes in the heart and differential RGS/GRK scaffolds coupling to different PKC/MAPK isoforms, explaining why a1A-AR stimulation is protective while chronic stimulation of the a1B-AR promotes cardiac damage.

描述（由申请人提供）：我们的目的是了解α 1-肾上腺素能受体（AR）亚型介导心脏保护与损伤的不同信号转导模式。a1-AR亚型（a1 A、a1 B和a1 D）是G蛋白偶联受体，其通过结合儿茶酚胺来介导交感神经系统。然而，对特定的子类型函数知之甚少。我们的研究表明，α 1-AR信号通路可能有助于心脏保护或损伤。最初认为α 1-AR拮抗剂可用于治疗由于交感神经超负荷引起的心力衰竭。然而，在抗高血压和降脂治疗预防心脏病发作试验中，使用非选择性α 1-AR拮抗剂使心力衰竭恶化并增加死亡率。与此相反，卡维地洛，一种α 1-和β-AR的拮抗剂，但对α 1B-AR亚型具有更高的亲和力，为慢性心力衰竭提供了有效的治疗，这表明亚型特异性信号传导可能有助于α 1-AR阻断的这些差异效应。由于α 1-AR拮抗剂在前列腺疾病中的使用，其治疗药物滥用和神经变性的潜力增加，确定α 1-AR亚型在心脏中的作用具有非常重要的临床意义。我们的实验室已经制造了独特的α 1-AR亚型转基因小鼠，并证明了心血管功能的差异调节。我们已经发表了a1 A-AR而不是a1 B-AR保护心脏免受缺血性损伤。慢性a1 B-AR刺激导致心脏功能障碍和炎症。我们已经确定了独特的途径，差异调节的α 1-AR亚型，如细胞凋亡，STAT 3激活，细胞因子分泌，这可能解释了如何差异控制心脏适应α 1-AR亚型。我们的研究可能会导致新的治疗策略的发展，以治疗心力衰竭和缺血。该提案的重点是心脏中的a1-AR亚型和与不同PKC/MAPK亚型偶联的差异RGS/GRK支架，解释了为什么a1 A-AR刺激具有保护作用，而a1 B-AR的慢性刺激促进心脏损伤。