Opioidergic System in Development of Heart Failure

描述（由申请方提供）：本提案的总体目标是研究阿片类药物系统的改变是否调节心力衰竭的发生和进展。虽然感染性心内膜炎是有据可查的，其临床特征也在阿片类药物成瘾者中得到了很好的描述，但很少有研究关注阿片类药物对感染性心内膜炎以外的心脏病的急性或慢性影响。同样，阿片系统在心脏功能恶化中的作用仍然完全是推测性的。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），并将在整个器官/动物水平的信息在细胞水平的基本信息整合。为了确定阿片系统参与心力衰竭的进展，我们将通过分子和药理学方法评估μ-，δ-和κ-阿片受体的表达和功能以及内源性阿片肽前体及其肽产物在心力衰竭进展的各个阶段的变化。此外，将通过超声心动图和左心室导管插入术沿着组织学和形态学技术评价长期阿片类药物/阿片类药物给药或阿片受体拮抗剂期间的心脏效应（即重塑和功能）。将使用易患肥厚型心肌病和心力衰竭的独特仓鼠品系来检测阿片类系统在心力衰竭发生和进展中的参与，以及每种阿片类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。这一建议的结果将提供新的见解心力衰竭和阿片系统之间的关系，调节慢性阿片类药物/阿片类药物的使用。阿片类药物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。了解心力衰竭中阿片系统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。这些发现可能有助于确定心力衰竭易感性或早期阶段的新诊断或生物标志物，从而允许易感患者的早期治疗和预防。此外，这些发现可能导致对长期暴露于阿片类药物/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.