SCOR IN HEART FAILURE

虽然充血性心脏的发病率、患病率和死亡率 失败似乎在增加，关于基本的 这一临床重要证候的发病机制(S)。这个 支持SCOR计划的总体假设是临床 充血性心力衰竭(CHF)由独特的可识别的 细胞和亚细胞成分的改变 心肌细胞。项目1将检查潜在的差异变化 在精心挑选的压力超负荷肥大触发器，传感器 以及在动物转化为充血性心力衰竭过程中出现的靶蛋白 该模型清楚地体现了这两种表型。项目2将 检测P-肾上腺素能受体基因变异的潜在作用 在早期和晚期人类充血性心力衰竭的病理生理学中。 项目3将研究心脏的基因调控和表达。 正常和心肌病心脏组织中sR-Ca~(2+)-ATPase的常规应用 分子生物学技术，过度表达野生动物的转基因小鼠 类型或突变的SR-ATPase泵以及早期和晚期充血性心力衰竭患者。 项目4将严格检查钙循环的功能 使用类似分析方法的调节蛋白磷蛋白 涉及创造高表达或低表达的转基因动物 正常和突变的磷蛋白。蚀变的平行研究 早期和晚期患者将进行磷脂蛋白水平测定 瑞士法郎。项目5将测试这样的假设：监管机构或 可磷酸化肌球蛋白轻链在正常和 使用项目3和项目3的平行方法的病理心功能 4涉及转基因模型和早、晚期心力衰竭患者。这个 整个整体项目将在其技术和 两个关键核心设施的分析推动力。《分子》 生理学核心将提供心肌细胞功能、钙 项目1-5的动力学和定量聚合酶链式反应。临床生理学 CORE将提供有创和无创的脑室评估 急性心肌梗死早期和晚期患者的心内膜功能和心肌活检 项目2-5的瑞士法郎。我们认为，拟议中的对 这个问题涉及分子生物学、细胞生物学和 综合生理学方法将对我们的 对充血性心脏的发病机制和治疗的认识 失败了。

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.