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.

已经建议在心力衰竭和人类失败心脏的动物模型中钙循环降低，至少部分地反映了肌浆网（SR）的钙隔离受损。 SR的钙隔离是由Ca2+ - 转移ATPase（SERCA2）介导的，其活性受磷团（PLN）的磷酸化状态可逆调节。去磷酸化的PLN是SERCA2和心脏收缩率的CA-亲和力的抑制剂，而PLN的磷酸化可缓解抑制作用。 PLN的水平已被证明是基础收缩力的主要决定因素，并且心脏对13个激动剂的反应。在人体心力衰竭中，相对于SERCA2的PLN水平增加，从而增加了Ca-Pump的Ca-亲和力和长时间松弛的抑制作用。此外，PLN的磷酸化状态降低，从而导致PLN和SR CA-Cycling进一步抑制抑制作用。 PLN磷酸化的降低反映了PLN磷酸酶1活性的增加，部分原因是抑制剂1（I-1）功能的去磷酸化和衰减。因此，这两种主要的CA调节蛋白成为我们在心力衰竭中的关注重点，重要的是确定PLN和I-1人类基因中是否可能发生遗传变异，例如点突变，这可能会改变其活性并改变疾病的临床过程。确实，我们最近确定了两个人类PLN突变，这些突变导致了年轻时的心肌病和心力衰竭。我们在这里建议继续研究PLN和1-1基因中其他突变的研究，并确定其功能意义和病理生理学相关性，即 利用表达系统和基因改变的小鼠。同时，将密切遵循具有鉴定突变的受试者，以评估其心脏功能，运动耐受性和力隔离关系（机械和放松恢复）。我们的发现将确定是否可以在PLN或1-1中的特定突变与特定的临床参数或心力衰竭的时间过程之间建立相关性。此外，这些研究将为特定遗传变异改变SR CA处理和心力衰竭功能的机制提供宝贵的见解。