Opioidergic System in Development of Heart Failure

描述(由申请人提供)：本提案的总体目标是调查阿片能系统的改变是否调节心力衰竭的发展和进展。尽管阿片类药物成瘾者会发生感染性心内膜炎，其临床特征也有很好的描述，但除了感染性心内膜炎外，很少有研究关注阿片类药物对心脏疾病的急性或慢性影响。同样，阿片能系统在心脏功能恶化中的作用仍然完全是推测的。将建立一个广泛的多学科方法，结合不同的技术(综合生理学、分子生物学和药理学)，并将细胞水平的基本信息与整个器官/动物水平的信息相结合。为了确定阿片能系统在心力衰竭进展过程中的作用，我们将通过分子和药理学方法评估心力衰竭进展过程中不同阶段内源性阿片肽前体及其多肽产物的表达和功能变化。此外，将通过超声心动图和左心室插管以及组织学和形态学技术来评估慢性阿片类药物/阿片类药物使用或阿片受体拮抗过程中的心脏效应(即重构和功能)。一种独特的易于患肥厚性心肌病和心力衰竭的仓鼠品系将被用来测试阿片能系统在心力衰竭的发生和进展中的参与，以及每种阿片受体类型如何调节慢性阿片类药物/阿片类药物滥用后心力衰竭的进展。这一提议的结果将为心力衰竭与阿片能系统之间的关系提供新的见解，因为长期阿片类药物/阿片类药物的使用调节了这一关系。阿片成瘾和心血管疾病在美国很普遍，也是代价高昂的公共卫生问题。了解阿片能系统在心力衰竭中的分子和细胞基础是阐明其在心血管疾病中作用的必要步骤。这些发现可能被证明有助于识别新的心力衰竭易感性或早期阶段的诊断或生物标志物，从而使易感患者能够更早地进行治疗和预防。此外，这些发现可能导致对长期服用阿片/阿片类药物的患者的医疗护理和治疗进行重新评估。

DESCRIPTION (provided by applicant): The overall objective of this proposal is to investigate whether the alterations in the opioidergic system modulate the development and progression of heart failure. Although infective endocarditis is well- documented to occur and its clinical features well described in opiate addicts, few studies have focused on the acute or chronic effects of opiates on heart diseases other than infective endocarditis. Likewise, the role of the opioidergic system in the deterioration of heart function remains entirely speculative. A broad multidisciplinary approach will be established that combines diverse techniques (integrative physiology, molecular biology, and pharmacology) and will integrate basic information at the cellular level with information at the whole organ/animal level. To ascertain the involvement of the opioidergic system in the progression of heart failure, we will assess mu-, delta-, and kappa-opioid receptor expression and functionality as well as alterations in endogenous opioid peptide precursors and their peptide products at various stages in the progression of heart failure via molecular and pharmacological methods. Furthermore, the cardiac effects (i.e, remodeling and function) during chronic opiate/opioid administration or opioid receptor antagonism will be evaluated by echocardiography and left ventricular catheterizations along with histological and morphological techniques. A unique hamster strain which is predisposed to hypertrophic cardiomyopathy and heart failure will be used to test the involvement of the opioidergic system in the development and progression to heart failure and how each opioid receptor type modulates the progression to heart failure following chronic opiate/opioid abuse. Results of this proposal will provide novel insights into the relationship between heart failure and the opioidergic system, as modulated by chronic opiate/opioid use. Opiate addiction and cardiovascular disease are prevalent as well as costly public health issues in the United States. Understanding the molecular and cellular basis of the opioidergic system in heart failure is a necessary step towards elucidating its role in cardiovascular disease. These findings may prove to be useful in identifying novel diagnostic or biomarkers for a predisposition to or early stages of heart failure, thus allowing earlier treatment and prevention in susceptible patients. Also, these findings may result in reassessment of medical care and treatment in patients exposed to chronic opiate/opioid administration.