Cardiac Beta-Adrenergic Adaptation in Pediatric Heart Failure

小儿心力衰竭的心脏β-肾上腺素能适应

• 批准号: 7707055
• 负责人: Shelley Deanne Miyamoto
• 金额: $ 18.92万
• 依托单位: UNIVERSITY OF COLORADO DENVER
• 依托单位国家: 美国
• 财政年份: 2009
• 资助国家: 美国
• 起止时间: 2009-09-01 至 2011-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7707055
• 关键词: Adrenergic Agents; Adrenergic Agonists; Adrenergic Receptor; Adult; Animal Model; Calmodulin; Cardiac; Cardiomyopathies; Catecholamines; Child; Childhood; Clinical; Clinical Research; Clinical Treatment; Data; Disease; Functional disorder; Future; Heart; Heart failure; Investigation; Isoproterenol; Knowledge; Measures; Mediating; Medical; MicroRNAs; Modeling; Molecular; Molecular Profiling; Morbidity - disease rate; Mus; Myocardial; Myocardium; Outcome; Pathology; Patients; Phosphorylation; Phosphotransferases; Play; Population; Primary idiopathic dilated cardiomyopathy; Regulatory Element; Role; Serum; Signal Pathway; Signal Transduction; Signaling Protein; System; Tissue Banking; Tissue Banks; Vulnerable Populations; adrenergic; clinical care; desensitization; improved; mortality; mouse model; public health relevance; receptor expression; response; Adrenergic Agents; Adrenergic Agonists; Adrenergic Receptor; Adult; Animal Model; Calmodulin; Cardiac; Cardiomyopathies; Catecholamines; Child; Childhood; Clinical; Clinical Research; Clinical Treatment; Data; Disease; Functional disorder; Future; Heart; Heart failure; Investigation; Isoproterenol; Knowledge; Measures; Mediating; Medical; MicroRNAs; Modeling; Molecular; Molecular Profiling; Morbidity - disease rate; Mus; Myocardial; Myocardium; Outcome; Pathology; Patients; Phosphorylation; Phosphotransferases; Play; Population; Primary idiopathic dilated cardiomyopathy; Regulatory Element; Role; Serum; Signal Pathway; Signal Transduction; Signaling Protein; System; Tissue Banking; Tissue Banks; Vulnerable Populations; adrenergic; clinical care; desensitization; improved; mortality; mouse model; public health relevance; receptor expression; response

DESCRIPTION (provided by applicant): Functional changes in the 2-adrenergic system play an important role in the pathophysiology of heart failure (HF) in adults. Experimental data has extensively defined many of the components involved in the 2-adrenergic receptor (2-AR) response in HF resulting in a shift of the clinical treatment paradigm to include 2-AR blocker therapy to improve morbidity and mortality. In children with heart failure, however, myocellular changes, including those in the 2-adrenergic system, are poorly understood. This fact proves to be a critical barrier for improving care and clinical outcomes in this vulnerable population. Although circulating catecholamine levels are elevated in both children and adults with HF, the lack of clinical benefit of betablocker (BB) therapy in children with HF is in stark contrast to the overwhelming evidence supporting beneficial BB effects in adults with HF and suggests that there may be important differences between children and adults in the myocellular response of the cardiac 2-adrenergic system to heart failure. Unfortunately, advances in our knowledge are hindered by the difficulty of performing clinical studies in pediatric populations and a lack of animal models specific to pediatric idiopathic cardiomyopathy. The central hypothesis of the current proposal is that the differences in clinical response to BB therapy is a product of differences in the response of the cardiac adrenergic system to HF in children and adults, both at the level of the AR as well as in its intracellular signaling pathways. Therefore the purpose of the current proposal is use our existing adult and pediatric explanted heart tissue banks [1] to identify key myocellular changes in cardiac 2-adrenergic receptors of pediatric patients with HF, and [2] measure the expression of central downstream signaling factors and microRNA effectors that are involved in the 2-adrenergic response in pediatric heart failure patients. In addition, the proposal will develop a mouse model for the response of the pediatric heart to the elevated catecholamine levels present in HF patients. Future investigations will use this model to dissect the molecular mechanisms of increased adrenergic stimulation in children with HF and thereby determine which therapies may be most beneficial in pediatric patients. PUBLIC HEALTH RELEVANCE: Heart failure is a deadly disease in children. In contrast to in adults, the changes that occur in the heart of children with heart failure are poorly understood. The current proposal will improve our understanding of the way a child's heart responds to heart failure so that we can improve medical treatment of this devastating disease.

描述（由申请人提供）：2-肾上腺素能系统的功能变化在成人心力衰竭（HF）的病理生理学中起重要作用。实验数据已广泛定义了HF中2-肾上腺素受体（2AR）反应的许多组件，从而导致临床治疗范式的转移以包括2AR阻滞剂治疗以提高发病率和死亡率。然而，在心力衰竭的儿童中，心肌变化，包括2-肾上腺素能体系的儿童，对心脏衰竭的变化知之甚少。事实证明，这是改善该脆弱人群的护理和临床结果的关键障碍。尽管HF儿童和成人的循环儿茶酚胺水平均升高，但HF儿童缺乏Betablocker（BB）疗法的临床益处与支持HF成人成人的压倒性BB效应形成鲜明对比，并暗示儿童和成人之间在肌纤维骨膜响应中可能存在重要的差异。不幸的是，我们所知的进步受到了在小儿种群中进行临床研究以及缺乏针对小儿特发性心肌病的动物模型的困难。当前建议的核心假设是，对BB治疗的临床反应差异是心脏肾上腺素能系统对儿童和成人HF反应差异的产物，无论是在AR及其细胞内信号传导途径上。因此，当前建议的目的是使用我们现有的成年和儿科外植物心脏组织库[1]来识别患有HF儿科患者心脏2-肾上腺素能受体的关键心肌变化，[2]衡量与2-肾上腺功能障碍患者相关的中央下游信号传导因素和微microRNA效应的表达。此外，该提案将开发小鼠模型，用于小儿心脏对HF患者存在的儿茶酚胺水平升高的反应。未来的研究将使用该模型来剖析HF儿童肾上腺素能刺激增加的分子机制，从而确定哪种疗法对小儿患者最有益。公共卫生相关性：心力衰竭是儿童致命疾病。与成年人相反，心力衰竭儿童中心发生的变化知之甚少。当前的建议将提高我们对孩子心脏对心力衰竭反应方式的理解，以便我们可以改善对这种毁灭性疾病的医疗治疗。