Angiogenic tissue engineering to limit post-infarction ventricular remodeling

描述（由申请人提供）：目的和具体目的心肌缺血和梗死导致心室重塑和心力衰竭，形成日益普遍的全球健康问题，其药物和手术治疗受到限制。非常需要创新疗法。本研究旨在研究和开发一种新的急性内源性血管重建疗法，该疗法上调内皮祖细胞（EPCs）并将其特异性靶向缺血心肌。心肌梗死后血管新生治疗增加心肌微循环将研究三个具体目标：1）动员和靶向化动EPCs以重建缺血心肌的血管。2)局部心肌生物力学特性的血管生成重建减轻心室重构和改善心功能。3)利用侵入性逐渐降低的临床可用技术进行内源性血运重建治疗的转化临床前大型动物模型试验。研究设计和方法：在心肌梗死和心室重构的大鼠模型中，将用粒细胞巨噬细胞集落刺激因子（GMCSF）刺激EPC的骨髓产生。通过直接心肌内给予有效的EPC趋化因子基质细胞衍生因子-11（SDF），将上调的EPC靶向缺血心脏。具体机制将阐明离体标记的EPCs以及心外SDF诱饵。将使用流式细胞术和免疫组织化学追踪内皮祖细胞。将用凝集素微血管造影术定量血管生成。将使用多巴酚丁胺负荷超声心动图确定微血管重建对缺血心肌收缩力的影响，并使用原子力显微镜和拉伸强度测量研究心肌组织特性。将在多个时间点使用超声心动图和腔内压力-容积电导微导管评估心室重构和心肌功能。将利用完善的缺血性心力衰竭绵羊模型研究SDF/GMCSF治疗在临床可转化动物模型中的疗效。将逐步评估从微创开胸术到Stiletto血管内注射导管再到经皮冠状动脉内给药的侵入性逐渐降低的临床可用输送技术，以优化细胞因子输送。 公共卫生相关性：心脏病发作及其并发症构成了一个全球性的健康问题，对此几乎没有高效的治疗方法。作为一种创新疗法，该提案寻求通过刺激骨髓中的血管祖细胞来放大身体的天然修复机制，然后将它们特异性地引导到心脏，以向受损的心肌生长新的灌注血管，并为人类疾病提供临床可行的治疗。

DESCRIPTION (provided by applicant): Objectives and Specific Aims Myocardial ischemia and infarction with resultant adverse ventricular remodeling and heart failure form an increasingly prevalent global health problem for which medical and surgical treatments are limited. Innovative therapies are greatly needed. This proposal seeks to investigate and develop a novel acute endogenous revascularization therapy which upregulates endothelial progenitor cells (EPCs) and specifically targets them to ischemic myocardium. This post- infarction angiogenic therapy to augment myocardial microcirculation will study three specific aims: 1) Mobilization and targeted chemokinesis of EPCs to revascularize ischemic myocardium. 2) Angiogenic reengineering of regional myocardial biomechanical properties to attenuate adverse ventricular remodeling and improve cardiac function. 3) Translational preclinical large animal model testing of endogenous revascularization therapy utilizing progressively less invasive, clinically-available technologies. Research Design and Methods: In a rat model of myocardial infarction and ventricular remodeling, bone marrow production of EPCs will be stimulated with granulocyte macrophage colony stimulating factor (GMCSF). The upregulated EPCs will be targeted to the ischemic heart with direct intramyocardial administration of the potent EPC chemokine stromal cell derived factor-11 (SDF). Specific mechanisms will be elucidated by ex vivo tagged EPCs as well as an extracardiac SDF decoy. EPCs will be tracked with flow cytometry and immunohistochemistry. Angiogenesis will be quantified with lectin microangiography. The impact of microrevascularization on ischemic myocardial contractility will be determined with dobutamine stress echocardiography and myocardial tissue properties will be studied utilizing atomic force microscopy and tensile strength measurements. Ventricular remodeling and myocardial function will be assessed at multiple time points with echocardiography and an intracavitary pressure-volume conductance microcatheter. A well-established ovine model of ischemic heart failure will be utilized to study the efficacy of SDF/GMCSF therapy in a clinically translatable animal model. A stepwise evaluation of progressively less invasive, clinically available delivery technologies, from minimally invasive thoracotomy to Stiletto endocardial injection catheter to percutaneous intracoronary administration, will be undertaken to optimize cytokine delivery. PUBLIC HEALTH RELEVANCE: Heart attack and its complications comprise a global health problem for which there are few highly effective treatments. As an innovative therapy, this proposal seeks to amplify the body's native repair machinery by stimulating vascular progenitor cells in the bone marrow and then specifically directing them to the heart to grow new perfusing blood vessels to the damaged heart muscle and providing a clinically viable treatment for human disease.