Bioenergetics in Hypertrophied and Remodeled Left Ventricle

左心室肥厚和重塑的生物能学

• 批准号: 8528711
• 负责人: Jianyi Zhang
• 金额: $ 62.28万
• 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/8528711
• 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。我们假设肌酸激酶 (CK) 和 ATP 酶的 ATP 生成率储备存在跨壁梯度，ENDO 中最低，导致 LVH 心脏中 ENDO 脆弱性。尽管人们对心肌修复的细胞疗法有着浓厚的兴趣，但迄今为止，大多数研究报告都是旨在修复或预防继发于冠状动脉疾病的心肌梗死的心脏的左心室功能障碍。鉴于超过50%的心脏移植CHF患者的病因是非缺血性的，因此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进行研究。细胞疗法有益作用的机制尚不明确。一致的发现是植入率低。然而，持续观察到受体心脏的左心室收缩功能的长期改善。因此，除了移植细胞的心肌再生之外，左心室功能的改善也可能与受体心肌蛋白顺性表达的变化有关。比较继发于压力超负荷或梗塞后左心室重塑的两种左心室肥厚猪模型，MSCs 移植对左心室收缩功能 (MRI) 的影响；心肌灌注、心肌氧合水平（1H-MRS）；每两周测量一次ATP周转率(31P-MRS)，持续8周，通过比较蛋白质组学检查受体心肌差异蛋白表达。具体目标是：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 周转率是否在 LVH 心脏的 ENDO 中发生最严重的改变，以及其严重程度是否与左室功能障碍的严重程度。 SA2。研究同种异体 MSC 移植的功能性益处是否伴随着患有或不患有缺血性冠状动脉疾病的 LVH 心脏的 ENDO 中 CK 和 ATPase 产生 ATP 能力的提高，以及这些功能性益处是否伴随着心肌的再生。移植的 MSC 和内源性 CPC。 SA3：检查细胞治疗的功能性有益效果是否与受体心肌的差异蛋白表达谱相关。我们将采用基于液相色谱质谱的最先进的比较蛋白质组学方法来定量确定蛋白质表达的变化，特别关注生长因子家族蛋白质和参与能量代谢的蛋白质。实验结果将首次阐明体内 LVH 心脏中通过 CK 和 ATPase 的 ATP 周转率的跨壁梯度。这些研究的结果将增进我们对心肌修复细胞治疗机制的理解，并为慢性心力衰竭患者提供更好的诊断和治疗方式。