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: 7460022
• 负责人: Y Joseph Woo
• 金额: $ 39.38万
• 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 2013-02-28
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7460022
• 关键词: Acute; Address; Anatomy; Animal Model; Animals; Apoptosis; Arteries; Atomic Force Microscopy; Attenuated; Biological Preservation; Biomechanics; Blood Vessels; Bone Marrow; Bypass; Cardiac; Cardiac Myocytes; Cardiomyopathies; Catheters; Characteristics; Clinical; Colony-Stimulating Factor Therapy; Condition; Dobutamine; Dobutamine Stress Echocardiography; Echocardiography; Elasticity; Engineering; Evaluation; Flow Cytometry; Granulocyte-Macrophage Colony-Stimulating Factor; Health; Heart; Heart failure; Human; Image; Immunohistochemistry; Infarction; Injection of therapeutic agent; Injury; Innovative Therapy; Invasive; Ischemia; Lead; Lectin; Marrow; Measurement; Mechanics; Medical; Metabolic; Methods; Microcirculation; Modeling; Monitor; Muscle Cells; Myocardial; Myocardial Infarction; Myocardial Ischemia; Myocardial tissue; Myocardium; Operative Surgical Procedures; Physiological; Production; Property; Public Health; Rattus; Research; Research Design; 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; Tumor-Associated Vasculature; Ventricular; Ventricular Function; Ventricular Remodeling; angiogenesis; base; chemokine; clinical efficacy; cytokine; functional decline; functional disability; human disease; improved; in vivo; injured; microangiography; novel; pre-clinical; pressure; progenitor; repaired; size

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(由申请者提供)：目的和具体目标心肌缺血和梗塞以及由此导致的不利的心室重构和心力衰竭形成了一个日益普遍的全球性健康问题，内科和外科治疗有限。创新疗法是非常需要的。该建议旨在研究和开发一种新的急性内源性血管重建术，该疗法上调内皮祖细胞(EPC)并特异性地将其靶向于缺血心肌。这种增加心肌微循环的血管生成疗法将研究三个具体目标：1)动员和靶向趋化内皮祖细胞，使缺血心肌血运重建。2)局部心肌生物力学性质的血管生成重组，以减轻不利的心室重构，改善心功能。3)利用逐渐减少的侵入性、临床可用的技术进行内源性血管重建术的临床前大动物模型试验。研究设计与方法：在心肌梗死和心室重构的大鼠模型中，粒细胞巨噬细胞集落刺激因子(GMCSF)将刺激骨髓内皮祖细胞的产生。上调的内皮祖细胞将通过直接心肌内注射有效的内皮祖细胞趋化因子基质细胞衍生因子11(SDF)来靶向缺血心脏。具体的机制将通过体外标记的内皮祖细胞以及心外SDF诱饵来阐明。用流式细胞仪和免疫组织化学方法对内皮祖细胞进行追踪。血管生成将通过凝集素微血管造影术进行量化。微血管重建术对缺血心肌收缩能力的影响将用多巴酚丁胺负荷超声心动图来确定，心肌组织特性将用原子力显微镜和拉伸强度测量来研究。超声心动图和腔内压力-容量电导微导管将在多个时间点评估心室重构和心肌功能。已建立的绵羊缺血性心力衰竭模型将被用来研究SDF/GMCSF治疗在临床可移植动物模型中的疗效。从微创开胸到斯蒂利托心内注射导管再到经皮冠状动脉内给药，将对侵入性逐渐降低的临床可用的给药技术进行逐步评估，以优化细胞因子的给药。 与公共卫生相关：心脏病发作及其并发症是一个全球性的健康问题，几乎没有非常有效的治疗方法。作为一种创新疗法，这项提议寻求通过刺激骨髓中的血管前体细胞，然后专门将它们引导到心脏，使其长出新的血管，将血管灌流到受损的心肌，从而放大人体固有的修复机制，并为人类疾病提供临床上可行的治疗方法。