SCOR IN HEART FAILURE

心力衰竭的评分

• 批准号: 2229635
• 负责人: Richard A. Walsh
• 金额: $ 129.46万
• 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/2229635
• 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.

虽然充血的发病率，患病率和死亡率 失败似乎增加了，关于基本的知之甚少 负责该临床重要综合征的机制。这 总体假设是该SCOR计划的基础 充血性心力衰竭（CHF）是由可识别的独特的 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 在精心选择的压力超负荷肥大触发器中，传感器 并使用动物过渡到CHF的靶蛋白 明确表现出这两种表型的模型。项目2将 检查P-肾上腺素受体的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节和表达 SR Ca2+ ATPase在正常的干旱心肌疗法心脏中使用常规心脏 分子生物学技术，过表达野生的转基因小鼠 类型或突变的SR ATPase泵和早期和晚期CHF的患者。 项目4将严格检查钙循环的功能 使用类似的分析方法调节蛋白磷酸 涉及产生具有过度或不渗透的转基因动物 正常和突变的磷酸兰班。平行研究 早期和晚期患者将进行磷团水平 瑞士法郎。项目5将检验监管或 磷酸化的肌球蛋白轻链在正常和 病理心脏功能采用平行方法进行项目3和 4涉及转基因模型和早期和晚期CHF的患者。这 整个项目的整个合奏将得到协助他们的技术和 两个关键核心设施的分析推力。分子 生理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 核心将提供心室的侵入性和无创评估 早期和晚期患者的功能和内膜活检 CHF针对项目2-5。 我们认为拟议的多层次攻击 涉及分子生物学，细胞生物学和 综合生理方法将对我们的 了解人类充血的发病机理和治疗 失败。