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

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）的病理生理学中发挥重要作用。实验数据广泛定义了 HF 中 2-肾上腺素能受体 (2-AR) 反应所涉及的许多成分，导致临床治疗范式发生转变，包括 2-AR 阻滞剂治疗，以改善发病率和死亡率。然而，在患有心力衰竭的儿童中，人们对肌细胞的变化（包括 2-肾上腺素能系统的变化）知之甚少。事实证明，这一事实是改善这一弱势群体的护理和临床结果的关键障碍。尽管心衰儿童和成人循环儿茶酚胺水平均升高，但β受体阻滞剂 (BB) 治疗心衰儿童缺乏临床益处，这与支持 BB 对心衰成人有益的证据形成鲜明对比，这表明可能儿童和成人之间心脏 2-肾上腺素能系统对心力衰竭的肌细胞反应存在重要差异。不幸的是，由于在儿科人群中进行临床研究的困难以及缺乏针对儿科特发性心肌病的动物模型，我们知识的进步受到阻碍。当前提议的中心假设是，对 BB 治疗的临床反应差异是儿童和成人心脏肾上腺素能系统对心力衰竭的反应差异的产物，无论是在 AR 水平还是在其细胞内信号通路。因此，当前提案的目的是利用我们现有的成人和儿童移植心脏组织库[1]来识别心力衰竭儿科患者心脏2-肾上腺素能受体的关键肌细胞变化，并[2]测量中央下游信号因子的表达以及参与儿科心力衰竭患者 2-肾上腺素能反应的 microRNA 效应器。此外，该提案还将开发一种小鼠模型，用于研究儿科心脏对心力衰竭患者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心力衰竭儿童肾上腺素能刺激增加的分子机制，从而确定哪些疗法可能对儿科患者最有益。公共卫生相关性：心力衰竭是儿童的一种致命疾病。与成人相比，心力衰竭儿童心脏发生的变化人们知之甚少。目前的提案将增进我们对儿童心脏对心力衰竭的反应方式的了解，以便我们能够改善这种毁灭性疾病的医疗治疗。