SCOR IN HEART FAILURE

虽然充血性心脏病的发病率、患病率和死亡率 失败似乎越来越多，对基本的 导致这种临床重要综合征的机制。的 该SCOR计划的总体假设是， 充血性心力衰竭（CHF）是由不同的可识别的 细胞和亚细胞成分的改变， 心肌细胞 项目1将检查潜在的差异性改变 在精心挑选的压力超负荷肥大触发器中， 以及使用动物在向CHF转变中发生的靶蛋白 这两个模型清楚地表明了这两种表型。项目2将 研究β-肾上腺素能受体遗传变异的潜在作用 早期和晚期人类充血性心力衰竭的病理生理学。 项目3将研究心脏的基因调控和表达， 常规心肌电生理技术对正常和心肌病心肌SR Ca ~（2+）ATP酶的研究 分子生物学技术，过表达野生型 型或突变型SR ATP酶泵与早期和晚期CHF患者的关系。 项目4将严格检查钙循环的功能 调节蛋白受磷蛋白使用类似的分析方法 包括产生过表达或低表达的转基因动物 正常和突变受磷蛋白的区别平行研究改变 受磷蛋白水平将在早期和晚期患者中进行。 瑞士法郎。项目5将检验监管或 磷酸化肌球蛋白轻链在正常和 使用与项目3平行的方法进行病理性心脏功能， 4涉及转基因模型和早期和晚期CHF患者。的 整个项目将在技术和 两个关键核心设施的分析推进。分子 生理学核心将提供心肌细胞功能、钙离子浓度、 项目1-5的动力学和定量PCR。临床生理学 核心将提供心室的有创和无创评估 功能和肌内膜活检的患者早期和晚期 项目2-5的瑞士法郎。 我们认为，拟议的多级攻击， 这个问题涉及到分子生物学，细胞生物学， 综合生理学方法将大大有助于我们 对充血性心脏病发病机制和治疗的认识 失败

Although the incidence, prevalence and mortality of congestive heart failure appear to be increasing, little is known regarding the basic mechanism(s) responsible for this clinically important syndrome. The overall hypothesis which underlies this SCOR Program is that clinical congestive heart failure (CHF) results from distinctive identifiable alterations in the cellular and subcellular components of the cardiomyocyte. Project 1 will examine potential differential alterations in carefully selected pressure overload hypertrophy triggers, transducers and target proteins which occur in the transition to CHF using an animal model which clearly manifests these two phenotypes. Project 2 will examine the potential role of genetic variants of P-adrenergic receptors in the pathophysiology of early and late human congestive heart failure. Project 3 will study the gene regulation and expression of the cardiac SR Ca2+ ATPase in normal arid cardiomyopathic hearts using conventional molecular biologic techniques, transgenic mice which overexpress wild type or mutated SR ATPase pumps and patients with early and late CHF. Project 4 will rigorously examine the function of the calcium cycling regulatory protein phospholamban using a similar analytic approach involving creation of transgenic animals with over- or underexpression of normal and mutant phospholamban. Parallel studies of altered phospholamban levels will be conducted in patients with early and late CHF. Project 5 will test the hypothesis that the regulatory or phosphorylatable myosin light chain plays a critical role in normal and pathologic cardiac function using a parallel approach to Project 3 and 4 involving transgenic models and patients with early and late CHF. The entire ensemble of projects will be assisted in their technical and analytical thrusts by two critical core facilities. The Molecular Physiology Core will provide analyses of cardiomyocyte function, calcium kinetics and quantitative PCR for Projects 1-5. The Clinical Physiology Core will provide invasive and noninvasive assessment of ventricular function and endomyocardial biopsies from patients with early and late CHF for Projects 2-5. We believe that the proposed multilevel attack on the problem which involves molecular biology, cell biology and integrative physiology approaches will contribute significantly to our understanding of the pathogenesis and treatment of human congestive heart failure.