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构

• 批准号: 9095414
• 负责人: Y Joseph Woo
• 金额: $ 38.07万
• 依托单位: STANFORD UNIVERSITY
• 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 2019-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9095414
• 关键词: Address; Animal Model; Animals; Automobile Driving; Biomechanics; Blood Vessels; Bone Marrow; Bypass; Cardiac; Cardiac Myocytes; Cell Survival; Cells; Characteristics; Chronic; Clinical; Clinical Trials; Coronary; Coronary artery; Country; Destinations; Disease; Elements; Encapsulated; Endothelium; Engineering; Extracellular Matrix; Fluorescence; Funding; Geometry; Goals; Health; Heart; Heart Injuries; Heart failure; Human; Hydrogels; Infarction; Injection of therapeutic agent; Injury; Institution; Knockout Mice; Ligation; Marrow; Mechanics; Mediating; Modeling; Myocardial; Myocardial Infarction; Myocardial Ischemia; Myocardial tissue; Myocardium; Nutrient; Optics; Oxygen; Patients; Performance; Perfusion; Physiological; Polymers; Property; Protein Chemistry; Protein Engineering; Rattus; Replacement Therapy; Role; Sheep; Signal Transduction; Smooth Muscle Myocytes; Source; Stem cells; Stromal Cell-Derived Factor 1; System; Techniques; Testing; Therapeutic; Tissue Engineering; Tissues; Transgenic Organisms; Translating; Translations; Ventricular; Ventricular Remodeling; Work; World Health; analog; angiogenesis; chemokine; clinically relevant; cytokine; design; global health; improved; injured; innovation; insight; minimally invasive; novel; operation; pre-clinical; progenitor; reconstitution; repaired; scaffold; spatial relationship; stem cell fate; therapeutic target

DESCRIPTION (provided by applicant): Myocardial ischemia, infarction, and heart failure constitute a disease spectrum which is rapidly becoming one of the foremost global health challenges. Current therapies focus upon pharmacologic optimization and macrorevascularization via PCI and CABG. Reconstructive and replacement therapies are limited in applicability or availability. A significant unmet need is that of microrevascularizatio. Repeated studies have demonstrated survival advantage in patients with robust collateralization. Thus the presence of endogenous revascularization and repair mechanisms exist and the benefits are clear; but the native potency is generally inadequate. In the initial funding period, we studied the primary effectors of endogenous microrevascularization, endothelial progenitor stem cells (EPC) and their potent chemokine stromal cell derived factor 1-alpha(SDF). We were able to significantly augment microvascular angiogenesis and improve local tissue biomechanical properties, ventricular geometry and cardiac function after myocardial ischemic injury. Via computational protein engineering, we then designed and synthesized a supra-efficient SDF analog as well as constructed a tissue engineered EPC extracellular-matrix simulating scaffold as an EPC delivery system that enhanced cell retention and survival. Elements of our work have been upscaled into a preclinical sheep model and also translated into a recently initiated human clinical trial at our institution. In this revised renewl application we propose to study in further depth the specific interactive mechanisms underlying SDF-mediated EPC neovasculogenesis, develop novel, cytokine and cell delivery platforms, and advance a potential therapeutic sustained release cytokine strategy in our preclinical sheep model. Specific Aim 1 will focus on elucidating mechanistic insights via a novel cardiac-specific SDF conditional knockout mouse, eGFP marrow reconstitution and EPC tracking, and optical fluorescence quantification of cellular level perfusion and biomechanical alterations. Specific Aim 2 will develop an innovative sustained release cytokine hydrogel composite and a unique smooth muscle cell-EPC bilevel cell sheet to deliver biologically supported EPCs to the heart. Specific Aim 3 will transition the hydrogel cytokine therapeutic strategy into a preclinical sheep model in a minimally invasive operative approach. We have generated the preliminary scientific components and assembled the team expertise to hopefully successfully achieve these goals.

描述（由申请人提供）：心肌缺血、梗塞和心力衰竭构成了一系列疾病，该疾病正迅速成为全球最重要的健康挑战之一。目前的治疗重点是通过 PCI 和 CABG 进行药理优化和大血管重建。重建和替代疗法的适用性或可用性受到限制。一个重要的未满足的需求是微血运重建。重复的研究已经证明具有强大抵押的患者具有生存优势。因此，内源性血运重建和修复机制的存在，其益处是显而易见的；但天然效力普遍不足。在最初的资助期间，我们研究了内源性微血运重建的主要效应器、内皮祖干细胞（EPC）及其强效趋化因子基质细胞衍生因子1-α（SDF）。我们能够显着增强微血管生成并改善心肌缺血损伤后的局部组织生物力学特性、心室几何形状和心脏功能。然后，通过计算蛋白质工程，我们设计并合成了超高效的 SDF 类似物，并构建了组织工程 EPC 细胞外基质模拟支架，作为 EPC 递送系统，增强细胞保留和存活。我们的工作要素已升级为临床前绵羊模型，并转化为我们机构最近启动的人体临床试验。在这个修订后的更新申请中，我们建议进一步深入研究 SDF 介导的 EPC 新生血管发生的具体相互作用机制，开发新型细胞因子和细胞递送平台，并在我们的临床前绵羊模型中推进潜在的治疗性持续释放细胞因子策略。具体目标 1 将重点通过新型心脏特异性 SDF 条件敲除小鼠、eGFP 骨髓重建和 EPC 追踪以及细胞水平灌注和生物力学改变的光学荧光定量来阐明机制见解。 Specific Aim 2 将开发一种创新的缓释细胞因子水凝胶复合材料和独特的平滑肌细胞-EPC 双层细胞片，将生物支持的 EPC 输送到心脏。具体目标 3 将通过微创手术方法将水凝胶细胞因子治疗策略转变为临床前绵羊模型。我们已经生成了初步的科学组件并汇集了团队的专业知识，希望能够成功实现这些目标。