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: 7772268
• 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/7772268
• 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; 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; Methods; Microcirculation; Modeling; Monitor; Muscle Cells; Myocardial; Myocardial Infarction; Myocardial Ischemia; Myocardial tissue; Myocardium; Operative Surgical Procedures; Physiological; Production; Property; 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; 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）：目标和特定目标是心肌缺血和梗死，导致的不良心室重塑和心力衰竭形成了越来越普遍的全球健康问题，医疗和手术治疗受到限制。非常需要创新的疗法。该提案旨在调查和开发一种新型的急性内源性血运重建疗法，该治疗上调内皮祖细胞（EPC），并专门针对缺血性心肌。这种梗塞后血管生成疗法增强心肌微循环将研究三个特定目的：1）EPCS的动员和靶向趋化因子，以血运性脑缺血性心肌质量。 2）区域心肌生物力学特性的血管生成重新设计，以减轻心室不良重塑并改善心脏功能。 3）使用逐渐侵入性，临床上可用的技术的内源性血运重建疗法的翻译临床前动物模型测试。研究设计和方法：在心肌梗塞和心室重塑的大鼠模型中，将用粒细胞巨噬细胞刺激因子（GMCSF）刺激EPC的骨髓产生。上调的EPC将以直接的EPC趋化因子基质细胞衍生因子11（SDF）的直接心膜内给药为目标。特定的机制将通过离体标记的EPC以及外心脏SDF诱饵来阐明特定机制。 EPC将通过流式细胞仪和免疫组织化学进行跟踪。血管生成将用凝集素显微镜图定量。小丁胺应激超声心动图确定微血管化对缺血性心肌收缩力的影响，将通过原子力显微镜和拉伸强度测量来研究心肌组织特性。心室重塑和心肌功能将在多个时间点评估，并具有超声心动图和腔内压力量电导电导率。良好的缺血性心力衰竭卵巢模型将用于研究SDF/GMCSF治疗在临床可翻译动物模型中的功效。将逐步评估从微创胸腔切开术到细高跟性心内膜注射导管再到经皮内部给药的逐步评估，从微创胸腔切开术到细胞质内给药，以优化细胞因子递送。 公共卫生相关性：心脏病发作及其并发症构成了一个全球健康问题，几乎没有高度有效的治疗方法。作为一种创新的疗法，该建议旨在通过刺激骨髓中的血管祖细胞来扩大人体的本地修复机械，然后专门将其引导到心脏，以将新的灌注血管生长为受损的心肌，并为人类疾病提供临床上可行的治疗方法。