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: 8853534
• 负责人: Y Joseph Woo
• 金额: $ 37.95万
• 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/8853534
• 关键词: 3-Dimensional; 3D Print; Address; Animal Model; Animals; Automobile Driving; Biomechanics; Blood Vessels; Bypass; Cardiac; Catheters; Cell Survival; Cell physiology; Cells; Characteristics; Chronic; Clinical; Clinical Trials; Coronary; Country; Destinations; Disease; Elements; Encapsulated; Endothelium; Engineering; Extracellular Matrix; Fibrin; Fluorescence; Funding; Gel; 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; Operative Surgical Procedures; Optics; Oxygen; Patients; Performance; Perfusion; Physiological; Preparation; Printing; Property; Protein Chemistry; Protein Engineering; Rattus; Replacement Therapy; Role; Sheep; Signal Transduction; Simulate; Smooth Muscle Myocytes; Stem cells; Stromal Cell-Derived Factor 1; Techniques; Technology; Testing; Therapeutic; Tissue Engineering; Tissues; Transgenic Organisms; Translating; Translations; Ventricular; Ventricular Remodeling; Vitronectin; Work; World Health; analog; angiogenesis; base; chemokine; clinically relevant; cytokine; design; global health; improved; injured; innovation; insight; minimally invasive; novel; operation; pre-clinical; progenitor; receptor; reconstitution; repaired; scaffold; spatial relationship; stem cell fate

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 initiated a project to embed EPCs in a vitronectin-based extracellular-matrix simulating scaffold to enhance cell retention and survival. Elements of this work have been upscaled into a preclinical sheep model and also translated into a recently initiated human clinical trial at our institution. In this renewal application we propose to study in further depth the specific interactive mechanisms underlying SDF-mediated EPC neovasculogenesis, develop novel, clinically translatable delivery platforms that enhance EPC function and survival, and refine these in our preclinical sheep model in preparation for potential human clinical investigation. Specific Aim 1 will focus on elucidating mechanistic insights via eGFP marrow reconstitution and tracking, a novel myocardial-specific SDF conditional knockout mouse, and optical fluorescence quantification of cellular level perfusion, oxygenation and energetics. Specific Aim 2 will develop innovative cellular composites based upon biologic extracellular matrix, cell sheet technology and synthetic 3-dimensional printed microscaffolds. Specific Aim 3 will transition this therapeutic strategy into a preclinical sheep model in minimally invasive operative and catheter- based approaches. 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、梗死和心力衰竭构成了一个疾病谱系，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进行药物优化和大血管重建。重建和替代疗法在适用性或可用性方面受到限制。一个重要的未满足的需求是微血管重建。反复的研究已经证明了强健侧支患者的生存优势。因此，存在内源性血运重建和修复机制，其益处是明确的；但其本身的效力通常是不够的。在最初的资助阶段，我们研究了内源性微血运重建的主要效应因子，内皮祖干细胞（EPC）及其强大的趋化因子基质细胞衍生因子1- α (SDF)。我们能够显著增强微血管新生，改善局部组织的生物力学特性，心室几何形状和心肌缺血损伤后的心脏功能。通过计算蛋白工程，我们设计并合成了一种超高效的SDF模拟物，并启动了一个项目，将EPCs嵌入基于体外连接蛋白的细胞外基质模拟支架中，以提高细胞的保留和存活。这项工作的要素已经扩大到临床前羊模型，也转化为最近在我们机构启动的人体临床试验。在这项更新申请中，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，开发新的临床可翻译的传递平台，增强EPC功能和存活，并在我们的临床前羊模型中完善这些平台，为潜在的人类临床研究做准备。特异性目标1将侧重于通过eGFP骨髓重构和跟踪、一种新型心肌特异性SDF条件敲除小鼠以及细胞水平灌注、氧合和能量学的光学荧光定量来阐明机制见解。Specific Aim 2将开发基于生物细胞外基质、细胞片技术和合成三维打印微支架的创新细胞复合材料。Specific Aim 3将把这种治疗策略转变为微创手术和导管为基础的临床前绵羊模型。我们已经产生了初步的科学组件，并汇集了团队的专业知识，希望能成功实现这些目标。