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.

在心力衰竭动物模型和人类心力衰竭模型中，钙循环的抑制被认为至少部分反映了肌浆网（SR）对钙的螯合作用受损。SR的钙螯合作用由钙转运ATP酶（SERCA 2）介导，其活性受受磷蛋白（PLN）磷酸化状态的可逆调节。脱磷酸化的PLN是SERCA 2的Ca-亲和力和心肌收缩力的抑制剂，而PLN的磷酸化减轻了抑制作用。PLN的水平已被证明是基础收缩性和心脏对β-受体激动剂的反应的主要决定因素。在人心力衰竭中，PLN相对于SERCA 2的水平增加，导致对Ca泵的Ca亲和力的抑制增加和舒张延长。此外，PLN的磷酸化状态降低，导致PLN的抑制功能增加，并进一步抑制SR Ca-循环。PLN磷酸化的减少反映了PLN磷酸酶1活性的增加，部分原因是去磷酸化和抑制剂1（I-1）功能的减弱。因此，这两个主要的钙调节蛋白成为我们关注的焦点，在心力衰竭，它是重要的，以确定是否遗传变异，如点突变，可能会发生在PLN和I-1人类基因，这可能会改变他们的活动和修改的临床过程中的疾病。事实上，我们最近发现了两种导致年轻时扩张型心肌病和心力衰竭的人类PLN突变。我们建议继续研究PLN和1-1基因中其他突变的鉴定，并确定其功能意义和病理生理学相关性， 利用表达系统和基因改变的小鼠。与此同时，将密切跟踪具有确定突变的受试者，以评估他们的心脏功能、运动耐力和力-间隔关系（机械和放松恢复）。我们的研究结果将确定PLN或1-1的特定突变与心力衰竭的特定临床参数或时间进程之间是否存在相关性。此外，这些研究将提供有价值的见解的机制，特定的遗传变异改变SR钙处理和功能在心力衰竭。