Frequency-dependent modulation of cardiac myofilament function in health/disease

健康/疾病中心肌丝功能的频率依赖性调节

基本信息

批准号：
9973777
负责人：
PAULUS ML JANSSEN
金额：
$ 38.03万
依托单位：
OHIO STATE UNIVERSITY
依托单位国家：
美国
项目类别：
财政年份：
2012
资助国家：
美国
起止时间：
2012-08-15 至 2024-05-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/9973777
关键词：
Adrenergic Agents Affect Age Area Behavior Biological Calcium Cardiac Chemosensitization Clinical Treatment Clinical assessments Contracts Coupling Data Data Reporting Disease Disease model Down-Regulation Etiology Event Exercise Exercise Tolerance Frequencies Functional disorder Genetic Grant Health Heart Heart failure Homeostasis Human Individual Kinetics Knowledge Laboratories Laboratory Animal Models Lead Link Literature Logistics Maps Mathematics Microfilaments Modality Modeling Molecular Myocardial Myocardium Oryctolagus cuniculus Pathologic Pathology Patients Pattern Phenotype Phosphorylation Post-Translational Protein Processing Proteins Pump Race Regulation Relaxation Rest Sodium-Calcium Exchanger Speed Testing Testis Tissue Sample Tissues Up-Regulation Ventricular Work base experimental study health difference human disease in vivo patient variability phospholamban pressure protein expression sex virtual

项目摘要

Project Summary In human heart failure, patient-to-patient variability is extremely well known, but extremely understudied. Relaxation disorders and aberrant force-frequency relationship (FFR) are both primary hallmarks of heart failure, and thus it is critical we understand the actual individual's dysfunction of these two parameters. It is imperative that we understand the actual molecular events in an affected individual, and not the purported molecular events that are based on group averages, that are known to be incorrect. Since clinical assessment and treatment is done on the single individual level, in this cycle of the grant we will work from the governing hypothesis that understanding of patient-specific protein expression and post-translational modification will allow us to understand the patient-specific relaxation dysfunction and aberrant FFR in failing human myocardium. To correlate a patient-specific profile with relaxation and FFR dysfunction, we propose to complete the following aims; 1) Continue procurement of failing and non- failing human myocardium, and assess relaxation behavior and the force-frequency relationship, 2) To assess individual protein levels and PTMs involved in the tri-modal regulation of relaxation and frequency-dependent contractile activation in human myocardium. We will assess levels and post-translational modifications in calcium- handling proteins, proteins involved in myofilament calcium sensitivity, and proteins involved in cross-bridge cycling kinetics, and 3) To assess the level of correlation between protein expression patterns and myocardial relaxation and force-frequency behavior in non-failing and failing human myocardium. Direct linking patient-specific molecular events to the pathophysiological situation in that patient will allow to better focus and target treatment of this debilitating disease.

项目摘要在人类心力衰竭中，患者对患者的变异性众所周知，但极度研究。放松障碍和异常的力量频率关系（FFR）都是心力衰竭的主要标志，因此我们了解这两个参数的实际个人功能障碍。我们必须了解受影响个体中的实际分子事件，而不是所谓的基于群体平均值的分子事件，已知是不正确的。由于临床评估和治疗是在单个个人级别上进行的，因此赠款的循环我们将从理解的理解中工作患者特定的蛋白质表达和翻译后修饰将使我们能够了解人类失败的患者特异性放松功能障碍和异常FFR 心肌。为了将患者特异性的轮廓与放松和FFR功能障碍相关联，我们建议完成以下目标； 1）继续采购失败和非 - 人体心肌失败，评估放松行为和力频率关系，2）评估三模式中涉及的个体蛋白水平和PTM 调节人类放松和频率依赖的收缩激活心肌。我们将评估钙的水平和翻译后修饰处理蛋白质，参与肌丝钙敏感性的蛋白质和蛋白质参与跨桥循环动力学，3）评估相关水平蛋白质表达模式与心肌松弛和力频率之间人类心肌的无效和失败的行为。直接连接患者特定的链接该患者的病理生理状况的分子事件将允许更好重点和目标治疗这种使人衰弱的疾病。