Calcium Cycling Protein Mutations in Human Heart Failure

人类心力衰竭中的钙循环蛋白突变

• 批准号: 7338017
• 负责人: Evangelia G Kranias
• 金额: $ 49.17万
• 依托单位: UNIVERSITY OF CINCINNATI
• 依托单位国家: 美国
• 财政年份: 2007
• 资助国家: 美国
• 起止时间: 2007-01-01 至 2009-12-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7338017
• 关键词: ATP phosphohydrolase; Address; Adrenergic Agents; Affect; Affinity; Age; Agonist; Animal Model; Attention; Attenuated; Biological Models; Ca(2+)-Transporting ATPase; Calcium; Cardiac; Cardiac Myocytes; Case-Control Studies; Cells; Clinical; Clinical Course of Disease; Code; Cytosol; Depressed mood; Dilated Cardiomyopathy; Exercise Tolerance; Failure; Family; Family Study; Genes; Genetic Polymorphism; Genetic Variation; Heart; Heart Contractilities; Heart Hypertrophy; Heart failure; Homeostasis; Human; Human Characteristics; In Vitro; Lead; Mechanics; Mediating; Membrane; Mental Depression; Modification; Mus; Mutation; Patients; Penetrance; Phenotype; Phosphoproteins; Phosphorylation; Point Mutation; Promoter Regions; Property; Protein Dephosphorylation; Protein phosphatase; Proteins; Pump; Purpose; Regulation; Relative (related person); Relaxation; Risk; Risk Assessment; Role; SERCA2a; Sarcoplasmic Reticulum; Source; System; Time; Variant; adrenergic; attenuation; base; case control; clinical effect; clinical phenotype; cohort; disorder risk; genetic regulatory protein; genetic variant; human study; in vivo Model; inhibitor/antagonist; insight; phospholamban; phospholamban phosphatase; promoter; research study; response

The depressed calcium cycling in animal models of heart failure and human failing hearts has been suggested to reflect, at least in part, the impaired calcium sequestration by the sarcoplasmic reticulum (SR). Calcium sequestration by the SR is mediated by a Ca2+-transport ATPase (SERCA2), whose activity is reversibly regulated by the phosphorylation status of phospholamban (PLN). Dephosphorylated PLN is an inhibitor of the Ca-affinity of SERCA2 and cardiac contractility, while phosphorylation of PLN relieves the inhibitory effects. The levels of PLN have been shown to be a major determinant of basal contractility and the heart's responses to 13-agonists. In human heart failure, the levels of PLN relative to SERCA2 are increased, resulting in increased inhibition of the Ca-pump's Ca-affinity and prolonged relaxation. In addition, the phosphorylation status of PLN is decreased, resulting in increased inhibitory function by PLN and further depression of SR Ca-cycling. The decreased PLN phosphorylation reflects increases in the PLN phosphatase 1 activity, partially due to dephosphorylation and attenuation of the inhibitor 1 (I-1) function. Thus, these two major Ca-regulatory proteins become our focus of attention in heart failure and it is important to determine whether genetic variations, such as point mutations, may occur in the PLN and I-1 human genes, which may alter their activities and modify the clinical course of the disease. Indeed, we have recently identified two human PLN mutations that led to dilated cardiomyopathy and heart failure at a young age. We propose here to continue our studies on identification of additional mutations in the PLN as well as the 1-1 genes and determine their functional significance and pathophysiological relevance, utilizing expression systems and genetically altered mice. In parallel, the subjects with the identified mutation will be closely followed to assess their cardiac function, exercise tolerance and force-interval relations (mechanical and relaxation restitution). Our findings will determine whether correlations may be established between a specific mutation in PLN or 1-1 and a specific clinical parameter or the time course of heart failure. Furthermore, these studies will provide valuable insights into the mechanisms by which specific genetic variants alter SR Ca-handling and function in heart failure.

在心力衰竭和人类心力衰竭的动物模型中，钙循环的抑制至少部分地反映了肌浆网(SR)对钙的固存的损害。肌质网钙离子的固存是由钙离子转运ATPase(SERCA2)介导的，该酶的活性受磷脂蛋白(PLN)磷酸化状态的可逆调节。去磷酸化的PLN是SERCA2的钙亲和力和心肌收缩能力的抑制剂，而PLN的磷酸化则解除这种抑制作用。PLN水平已被证明是基础收缩能力和心脏对13种激动剂反应的主要决定因素。在人类心力衰竭中，PLN相对于SERCA2的水平增加，导致钙泵钙亲和力的抑制增加，从而延长了松弛时间。此外，PLN的磷酸化状态降低，导致PLN的抑制功能增强，并进一步抑制SR钙循环。PLN磷酸化的降低反映了PLN磷酸酶1活性的增加，部分原因是去磷酸化和抑制物1(I-1)功能的减弱。因此，这两种主要的钙调节蛋白成为我们在心力衰竭中关注的焦点，确定PLN和I-1人类基因是否可能发生遗传变异，如点突变，可能会改变它们的活性，改变疾病的临床病程，这是很重要的。事实上，我们最近发现了两个人类PLN突变，它们导致了扩张型心肌病和年轻时的心力衰竭。我们建议继续我们的研究，鉴定PLN和1-1基因中的其他突变，并确定它们的功能意义和病理生理相关性。 利用表达系统和转基因小鼠。同时，将密切跟踪发现突变的受试者，以评估他们的心脏功能、运动耐量和力量-时间间隔关系(机械和松弛恢复)。我们的发现将确定PLN或1-1的特定突变是否可能与特定的临床参数或心力衰竭的时间进程之间建立关联。此外，这些研究将为特定基因变异改变SR钙处理和心力衰竭功能的机制提供有价值的见解。