Bioenergetics in Hypertrophied and Remodeled Left Ventricle

左心室肥厚和重塑的生物能学

• 批准号: 8676931
• 负责人: Jianyi Zhang
• 金额: $ 64.11万
• 依托单位: UNIVERSITY OF MINNESOTA
• 依托单位国家: 美国
• 财政年份: 2012
• 资助国家: 美国
• 起止时间: 2012-08-10 至 2016-05-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8676931
• 关键词: ATP phosphohydrolase; Allogenic; Animal Model; Bioenergetics; Blood Vessels; Blood flow; Buffers; Cardiac; Cell Differentiation process; Cell Transplantation; Cells; Clinical Trials; Congestive Heart Failure; Contracts; Coronary Arteriosclerosis; Coronary Stenosis; Coronary artery; Coronary heart disease; Creatine Kinase; Diagnostic; Energy Metabolism; Engraftment; Etiology; Family suidae; Functional disorder; Growth Factor; Heart; Heart Transplantation; Hypertrophy; Infarction; Ischemia; Lead; Left; Left Ventricular Hypertrophy; Left Ventricular Remodeling; Left ventricular structure; Magnetic Resonance Imaging; Measures; Mesenchymal Stem Cell Transplantation; Mesenchymal Stem Cells; Methods; Modality; Modeling; Molecular Profiling; Muscle Cells; Myocardial; Myocardial Contraction; Myocardial Infarction; Myocardial perfusion; Myocardium; Natural regeneration; Oxidative Stress; Pathway interactions; Patients; Performance; Perfusion; Post-Translational Protein Processing; Pre-Clinical Model; Production; Protein Family; Proteins; Proteomics; Reporting; Research; Safety; Secondary to; Severities; Signal Pathway; Stem cell transplant; Stem cells; Stress; System; Systole; Therapeutic; Time; Ventricular; base; clinically relevant; comparative; data acquisition; density; design; follow-up; functional outcomes; improved; in vivo; interest; liquid chromatography mass spectrometry; pressure; prevent; protein expression; repaired; research study; response; sex

DESCRIPTION (provided by applicant): The inner layers of the left ventricular wall (ENDO) are known to be the most susceptible to oxidative stresses. We hypothesize that there is transmural gradient of reserves of ATP production rate via both creatine kinase (CK) and ATPase, which is the lowest in ENDO that results in the ENDO vulnerability in LVH hearts. Despite the intense interest in cellular therapy for myocardial repair, the majority of research reports to date have been designed to repair or prevent LV dysfunction in hearts with myocardial infarction secondary to coronary arteries diseases. Given the fact that more than 50% of heart transplant CHF patients whose etiology is nonischemic, studies using nonischemic large animal model is urgently needed before pursuing large scale clinical trials. The mechanisms underlying the beneficial effects of cellular therapy are not well defined. It is a consistent finding that the engraftment rate is low. However, the long term improvement of the LV contractile function of the recipient heart is consistently observed. Therefore, in addition to the myocardial regeneration from the engrafted cells the improved LV chamber function is also likely related to the changes of the recipient myocardial protein deferential expression. Comparing two swine models of LVH secondary to pressure overload or to postinfarction LV remodeling, the effects of MSCs transplantation on LV contractile function (MRI); myocardial perfusion, myocardial oxygenation level (1H-MRS); and ATP turnover rate (31P- MRS) will be measured biweekly for 8 weeks, the recipient myocardial differential protein expression will be examined by comparative proteomics. The specific aims are: SA1. Using the recently developed T1-nom P-31 magnetization saturation transfer (MST) methods to examine whether the myocardial ATP turnover rate via CK and ATPase are most severely altered in the ENDO of LVH hearts, and whether the severity of which is linearly related to the severity of the LV dysfunction. SA2. To examine whether the functional beneficial effects of allogenic MSC transplantation are accompanied by the improvement of ATP production capacity via CK and ATPase in the ENDO of LVH hearts with or without ischemic coronary artery diseases, and whether these functional benefits are accompanied by regeneration of myocardium from both engrafted MSCs as well as endogenous CPCs. SA3: To examine whether the functional beneficial effects of cellular therapy are associated with the differential protein expression profle of the recipient myocardium. We will employ cutting edge liquid chromatography mass spectrometry-based comparative proteomics method to quantitatively determine the changes in the protein expression with a special emphasis on growth factors family proteins and proteins involved in energy metabolism. The findings of the experiments will elucidate for the first time, the transmural gradient of ATP turnover rate via both CK and ATPase in the in vivo LVH hearts. The findings of these studies will advance our understanding of the mechanisms of cellular therapy in myocardial repair, and lead to better diagnostic and therapeutic modalities for CHF patients.

描述（由申请人提供）：已知左心室壁（Endo）的内层最容易受到氧化应激的影响。我们假设通过肌酸激酶（CK）和ATPase具有透射式ATP生产率的梯度，这是Endo中最低的，这导致LVH心脏中的endo脆弱性。尽管对心肌修复的细胞疗法非常感兴趣，但迄今为止，大多数研究报告旨在修复或防止冠状动脉疾病继发性心肌梗塞心脏的LV功能障碍。鉴于这一事实是，在进行大规模临床试验之前，迫切需要使用非缺血性大动物模型的病因为非流行病学的心脏移植CHF患者。细胞疗法的有益作用的基础机制尚未很好地定义。这是一个一致的发现，即植入率很低。但是，始终观察到受体心脏的LV收缩功能的长期改善。因此，除了植入细胞的心肌再生外，改善的LV腔室功能也可能与受体心肌蛋白递延表达的变化有关。将第二个LVH的猪模型与压力超负荷或发射后LV重塑进行比较，MSC移植对LV收缩功能（MRI）的影响；心肌灌注，心肌充氧水平（1H-MRS）； ATP周转率（31p- MRS）将每两周测量8周，受体心肌差异蛋白表达将通过比较蛋白质组学检查。具体目的是：SA1。使用最近开发的T1-NOM P-31磁化饱和转移（MST）方法来检查通过CK和ATPase的心肌ATP转换速率是否在LVH心脏的内膜中最大变化，以及其严重程度是否与LV功能障碍的严重程度线性相关。 SA2。要检查同种异体MSC移植的功能有益作用是否伴随着通过CK和ATPase提高ATP生产能力，而LVH心脏中有或没有缺血性冠状动脉疾病的Endo，以及这些功能益处是否伴随着两种雕刻MSCS的心肌再生以及Endocenos Endostocs CPSS的伴随。 SA3：检查细胞疗法的功能有益作用是否与受体心肌的差异蛋白表达分布有关。我们将采用基于较切的液相色谱法质谱法比较蛋白质组学方法来定量确定蛋白质表达的变化，并特别强调了与能量代谢有关的生长因子家族蛋白和蛋白质。实验的发现将首次阐明，即通过CK和ATPase在体内LVH心脏中通过CK和ATPase的透射率梯度。这些研究的发现将提高我们对心肌修复中细胞治疗机制的理解，并为CHF患者提供更好的诊断和治疗方式。