SCOR IN HEART FAILURE

心力衰竭的评分

• 批准号: 2857832
• 负责人: Gerald W. Dorn
• 金额: $ 157.69万
• 依托单位: UNIVERSITY OF CINCINNATI
• 依托单位国家: 美国
• 财政年份: 1995
• 资助国家: 美国
• 起止时间: 1995-02-17 至 1999-12-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/2857832
• 关键词: cellular pathology; congestive heart failure

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.

尽管充血性心脏病的发病率、患病率和死亡率 故障似乎在增加，但人们对基本原理知之甚少 造成这种临床上重要综合征的机制。这 该 SCOR 计划的总体假设是临床 充血性心力衰竭（CHF）是由独特的可识别疾病引起的 细胞和亚细胞成分的改变 心肌细胞。 项目 1 将检查潜在的差异改变 在精心挑选的压力过载肥大触发器、传感器中 以及使用动物向 CHF 转变过程中发生的靶蛋白 模型清楚地体现了这两种表型。项目2将 检查 P-肾上腺素受体遗传变异的潜在作用 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 使用常规方法对正常干旱心肌病心脏中的 SR Ca2+ ATPase 进行观察 分子生物学技术，过度表达野生型的转基因小鼠 型或突变的 SR ATP 酶泵以及早期和晚期 CHF 患者。 项目4将严格检查钙循环的功能 使用类似的分析方法分析调节蛋白受磷蛋白 涉及创建过度表达或表达不足的转基因动物 正常和突变的受磷蛋白。改变的平行研究 将对早期和晚期患者进行受磷蛋白水平检测 瑞士法郎。项目 5 将检验以下假设：监管或 可磷酸化的肌球蛋白轻链在正常和 使用与项目 3 平行的方法来评估病理心脏功能 4 涉及转基因模型以及早期和晚期 CHF 患者。这 整个项目组将在技术和技术方面得到协助 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、钙的分析 项目 1-5 的动力学和定量 PCR。临床生理学 Core 将提供心室的有创和无创评估 早期和晚期患者的功能和心内膜心肌活检 项目 2-5 瑞士法郎。 我们认为，拟议的多层次攻击 该问题涉及分子生物学、细胞生物学和 综合生理学方法将大大有助于我们 了解人类充血性心脏病的发病机制和治疗 失败。