Angiogenic tissue engineering to limit post-infarction ventricular remodeling

血管生成组织工程限制梗死后心室重塑

• 批准号: 8230794
• 负责人: Y Joseph Woo
• 金额: $ 38.98万
• 依托单位: UNIVERSITY OF PENNSYLVANIA
• 依托单位国家: 美国
• 财政年份: 2008
• 资助国家: 美国
• 起止时间: 2008-03-15 至 2013-11-28
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8230794
• 关键词: Acute; Address; Anatomy; Animal Model; Animals; Apoptosis; Arteries; Atomic Force Microscopy; Attenuated; Biological Preservation; Biomechanics; Blood Vessels; Bone Marrow; Bypass; CD34 gene; Cardiac; Cardiac Myocytes; Cardiomyopathies; Catheters; Characteristics; Clinical; Colony-Stimulating Factor Therapy; Dobutamine; Dobutamine Stress Echocardiography; Echocardiography; Elasticity; Engineering; Evaluation; Flow Cytometry; Granulocyte-Macrophage Colony-Stimulating Factor; Heart; Heart failure; Human; Image; Immunohistochemistry; Infarction; Injection of therapeutic agent; Injury; Innovative Therapy; Ischemia; Lead; Lectin; Marrow; Measurement; Mechanics; Medical; Metabolic; Microcirculation; Modeling; Monitor; Muscle Cells; Myocardial; Myocardial Infarction; Myocardial Ischemia; Myocardial tissue; Myocardium; Operative Surgical Procedures; PECAM1 gene; Physiological; Production; Property; Rattus; Research; Research Design; Research Methodology; Rest; Rodent; Smooth Muscle Myocytes; Stem cells; Stress; Stromal Cell-Derived Factor 1; Stromal Cells; System; Techniques; Technology; Tensile Strength; Testing; Therapeutic; Thoracotomy; Time; TimeLine; Tissue Engineering; Tissues; Translations; Vascular Endothelial Growth Factor Receptor-2; Ventricular; Ventricular Function; Ventricular Remodeling; angiogenesis; base; chemokine; cytokine; effective therapy; functional decline; functional disability; global health; human disease; improved; in vivo; injured; microangiography; minimally invasive; neovasculature; novel; pre-clinical; preclinical efficacy; pressure; progenitor; public health relevance; repaired

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.

描述（由申请人提供）： 目的和具体目标 心肌缺血和梗塞以及由此产生的不良心室重构和心力衰竭形成了日益普遍的全球健康问题，对此药物和手术治疗都受到限制。非常需要创新疗法。该提案旨在研究和开发一种新型急性内源性血运重建疗法，该疗法可上调内皮祖细胞（EPC）并专门针对缺血心肌。这种增强心肌微循环的梗死后血管生成疗法将研究三个具体目标：1) EPC 的动员和靶向趋化作用以使缺血心肌血运重建。 2）局部心肌生物力学特性的血管生成再造，以减轻不利的心室重塑并改善心脏功能。 3) 利用渐进的侵入性较小的临床可用技术，对内源性血运重建疗法进行临床前大型动物模型转化测试。研究设计和方法：在心肌梗塞和心室重塑的大鼠模型中，用粒细胞巨噬细胞集落刺激因子（GMCSF）刺激骨髓中EPC的产生。通过直接心肌内注射有效的 EPC 趋化因子基质细胞衍生因子 11 (SDF)，上调的 EPC 将靶向缺血心脏。具体机制将通过离体标记的 EPC 以及心外 SDF 诱饵来阐明。 EPC 将通过流式细胞术和免疫组织化学进行追踪。血管生成将通过凝集素微血管造影进行量化。微血运重建对缺血性心肌收缩力的影响将通过多巴酚丁胺负荷超声心动图确定，并且将利用原子力显微镜和拉伸强度测量来研究心肌组织特性。将通过超声心动图和腔内压力-容积电导微导管在多个时间点评估心室重塑和心肌功能。将利用完善的绵羊缺血性心力衰竭模型来研究 SDF/GMCSF 治疗在临床可转化动物模型中的疗效。将逐步评估渐进的微创、临床可用的递送技术，从微创开胸术到Stiletto心内膜注射导管再到经皮冠状动脉内给药，以优化细胞因子的递送。 公共卫生相关性：心脏病及其并发症是一个全球性健康问题，目前几乎没有高效的治疗方法。作为一种创新疗法，该提案旨在通过刺激骨髓中的血管祖细胞，然后将其特异性引导至心脏，为受损的心肌生长新的灌注血管，从而增强人体的天然修复机制，为人类疾病提供临床上可行的治疗方法。