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（由适用提供）：我们的目标是了解A1-肾上腺素受体（AR）子类型介导保护与心脏损害的差分信号转导范例。 A1-AR亚型（A1A，A1B和A1D）是G蛋白偶联受体，可通过结合儿茶酚胺来介导交感神经系统。但是，关于特定的亚型函数知之甚少。我们的研究表明，A1-AR信号通路可能有助于心脏保护或损害。最初认为A1-AR拮抗剂可用于治疗同情超负荷引起的心力衰竭。但是，在防止心脏病发作试验的降压和降低脂质治疗中，使用非选择性A1-AR拮抗剂会加剧心力衰竭和死亡率增加。相比之下，Carvedilol是A1-和`ARS的拮抗剂，但对A1B-AR亚型的亲和力较高，为慢性心力衰竭提供了有效的治疗方法，这表明亚型特异性信号传导可能有助于A1-AR阻断的这些差异效应。由于使用A1-AR拮抗剂在前列腺疾病中，它增加了治疗药物滥用和神经退行性的潜力，确定A1-AR亚型在心脏中的作用具有非常重要的临床意义。我们的实验室制造了A1-AR亚型的独特转基因小鼠，并显示了心血管功能的差异调节。我们已经发表了A1A-AR，但没有A1B-AR保护心脏免受缺血性损伤。慢性A1B-AR模拟导致心脏功能障碍和炎症。我们已经确定了由A1-AR亚型（例如凋亡，STAT3激活和细胞因子分泌）不同调节的独特途径，这些途径可能解释了A1-AR亚型如何不同地控制心脏适应。我们的研究可能导致发展新的治疗策略来治疗心力衰竭和缺血。该提案的重点是心脏中的A1-AR亚型，以及与不同的PKC/MAPK同工型耦合的差异RGS/GRK支架，解释了为什么A1A-AR刺激受到慢性刺激而促进心脏损害。