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：
7982876
负责人：
DIANNE M PEREZ
金额：
$ 39.25万
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 2014-04-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/7982876
关键词：
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 Heart Heart failure Hypertrophy IL6 gene Imidazolines In Vitro Inflammation Injury Interleukin-6 Ischemia Laboratories Lead Light Lipids 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 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. PUBLIC HEALTH RELEVANCE: This proposal will demonstrate and determine the mechanism by which the a1A- adrenergic receptor can protect the heart against ischemia and induce an adaptive hypertrophy that protects against apoptosis. In light of clinical trials which indicate that blockage of a1-ARs is deleterious for heart failure, but are commonly used to treat prostatic hyperplasia, we need to determine the exact roles of the a1-AR subtypes in cardiac regulation using animal models that will give definitive answers.

描述（由申请人提供）：我们的目标是了解α1-肾上腺素受体（AR）亚型通过G蛋白偶联介导α1-AR亚型（a1A、a1B和a1D）对心脏的保护和损伤的差异信号转导范例。然而，我们的研究表明，α1-AR 信号通路可能有助于介导交感神经系统。最初认为α1-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，但在预防心脏病发作的抗高血压和降脂治疗试验中，使用非选择性α1-AR。拮抗剂加剧了心力衰竭并增加了死亡率，相反，a1-和¿的拮抗剂卡维地洛。 -ARs 但对 a1B-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方法，这表明亚型特异性信号传导可能导致 a1-AR 阻断的这些差异效应，因为 a1-AR 拮抗剂的使用。前列腺疾病，其治疗药物滥用和神经退行性疾病的潜力不断增加，确定 a1-AR 亚型在心脏中的作用具有非常重要的临床意义，我们的实验室已经制作了独特的 a1-AR 亚型转基因小鼠，并证明了 a1-AR 亚型的差异调节。我们已经发表，a1A-AR 但不是 a1B-AR 可以保护心脏免受慢性 a1B-AR 刺激导致心脏功能障碍和炎症。 AR 亚型，例如细胞凋亡、STAT3 激活和细胞因子分泌，这可能解释 a1-AR 亚型如何差异控制心脏适应，我们的研究可能会导致开发治疗心力衰竭和心力衰竭的新治疗策略。该提案重点关注心脏中的 a1-AR 亚型以及与不同 PKC/MAPK 同工型耦合的差异 RGS/GRK 支架，解释了为什么 a1A-AR 刺激具有保护作用，而长期刺激 a1B-AR 会促进心脏损伤。公共健康相关性：根据临床试验表明，α1-肾上腺素能受体的阻断是有害的，该提案将证明并确定α1A-肾上腺素能受体保护心脏免受缺血并诱导适应性肥大以防止细胞凋亡的机制。用于治疗心力衰竭，但通常用于治疗前列腺增生，我们需要使用动物模型确定 a1-AR 亚型在心脏调节中的确切作用，从而给出明确的答案。