Restoration of Myocardial Healing by Extracellular Matrix Remodeling

通过细胞外基质重塑恢复心肌愈合

• 批准号: 9324066
• 负责人: MARK ALAN SUSSMAN
• 金额: $ 18.21万
• 依托单位: SAN DIEGO STATE UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2006
• 资助国家: 美国
• 起止时间: 2006-09-01 至 2019-07-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9324066
• 关键词: Adoptive Transfer; Adult; Aging; Apoptosis; Apoptotic; Appearance; Binding; Biology; Cardiac; Cardiac Myocytes; Catecholamines; Cell Communication; Cell Survival; Cell physiology; Cell surface; Cells; Cicatrix; Collaborations; Collagen; Data; Dependovirus; Development; Engineering; Engraftment; Environment; Extracellular Matrix; Extracellular Matrix Proteins; FOS gene; Fibronectin Receptors; Fibronectins; Focal Adhesion Kinase 1; Functional disorder; Goals; Healthcare Systems; Heart; Heart Diseases; Heart Hypertrophy; Heart failure; Hypertrophy; Immediate-Early Genes; Immunoblot Analysis; Immunohistochemistry; In Vitro; Infarction; Inhibition of Apoptosis; Injury; Innovative Therapy; Instruction; Integrins; Intravenous; JUN gene; Maintenance; Malignant Neoplasms; Mediating; Mitogen-Activated Protein Kinases; Modeling; Modification; Molecular; Myocardial; Myocardial Infarction; Myocardium; Natural regeneration; Oxidative Stress; Participant; Pathologic; Pathway interactions; Performance; Phosphorylation; Phosphotransferases; Public Health; Receptor Activation; Recruitment Activity; Regenerative Medicine; Regimen; Regulation; Research; Resistance; Reverse Transcriptase Polymerase Chain Reaction; Role; Signal Transduction; Small Interfering RNA; Starvation; Stem cells; Techniques; Therapeutic; Therapeutic Intervention; Tissues; Translating; United States; biological adaptation to stress; c-myc Genes; cardiac repair; cardiogenesis; cell growth; clinical application; expectation; extracellular; gene induction; healing; improved; in vivo; innovation; knock-down; mortality; mouse model; novel; overexpression; programs; proto-oncogene protein pim; proto-oncogene protein pim-1; receptor expression; repaired; response; response to injury; restoration; spatiotemporal; survivin; vector

Discovery of cardiac progenitor cells (CPCs) in the adult tieart hias led to tieightened expectations for novel treatments of cardiac disease. However, adoptive transfer of CPCs results only in transient improvement of cardiac performance as most donated cells fail to persist in the hostile milieu of the ischemic scar. Whereas approaches focus upon enhancing capabilities of stem cells, engineering of the damaged myocardium is a valid alternative strategy to enhance myocardial repair and regeneration. Extracellular matrix (ECM) proteins are pivotal components of the myocardial environment important in maintenance of cellular function. The overall goal of this proposal is to improve the survival, proliferation, recruitment, and persistence of CPC in the damaged myocardium by modification of fibronectin (Fn) expression, an ECM protein which correlates highly with spatio-temporal appearance of CPCs in the heart. Our preliminary data delineate a Fn-a5pi-FAK- Pim-1 signaling cascade regulating CPC growth and survival. Relevance of Fn, aSpi, FAK and Pim-1 in cardiomyocyte biology are well accepted, however, nothing is known about this pathway in CPCs. The short term goal is to understand the significance of the Fn-a5pi-FAK-Pim-1 pathway in CPCs under pathological conditions and extrapolate an innovative therapeutic approach to engineer the extracellular environment of the damaged myocardium to enhance regeneration and repair. Translational potential will be explored using an adeno-associated virus type 9 (AAV9) vector expressing a f unctional collagen-tethered Fn fragment to enhance CPC survival, proliferation, recruitment, and engraftment. Our specific aims are: 1) The Fn-a5(31- FAK-Pim-1 signaling axis is triggered following cardiomyopathic injury in vivo, 2) a5(31-integrin receptor activation by Fn induces i mmediate ea riy s tress r esponses, s urvival, and pr oliferation v ia FAK-Pim-1 signaling in CPCs, 3) Robust and persistent CPC-dependent regeneration is mediated by overexpression of a collagen binding Fn fragment delivered by cardiotropic AAV9 vector. Significance is to define beneficial aspects of endogenous repair to injury response. The long term goal is to translate the Fn fragment expressing AAV9 regimen into clinical application to establish innovative therapy for regenerative medicine. RELEVANCE (See instructions): Heart disease, especially heart failure is a major public health issue in the United States with a considerable burden for the health care system. Despite recent progress in understanding the pathophysiology, heart failure still carries a 5-year mortality that rivals most cancers. This proposal focuses upon understanding how the environment of the damaged heart can impact upon repair and regeneration on a cellular and molecular level.

在成体动脉瘤中发现心脏祖细胞（CPC），引发了对新型心脏祖细胞的期望。 心脏病的治疗。然而，CPC 的过继转移只能暂时改善 由于大多数捐赠的细胞无法在缺血性疤痕的恶劣环境中持续存在，因此心脏功能受到影响。然而 方法侧重于增强干细胞的能力，受损心肌的工程是一种 增强心肌修复和再生的有效替代策略。细胞外基质 (ECM) 蛋白 是心肌环境的关键组成部分，对于维持细胞功能非常重要。这 该提案的总体目标是改善 CPC 的生存、扩散、招募和持久性 通过纤连蛋白 (Fn) 表达的修饰来修复受损的心肌，纤连蛋白 (Fn) 是一种 ECM 蛋白，与 与心脏中 CPC 的时空表现高度相关。我们的初步数据描绘了 Fn-a5pi-FAK- Pim-1 信号级联调节 CPC 生长和存活。 Fn、aSpi、FAK 和 Pim-1 的相关性 心肌细胞生物学已被广泛接受，然而，人们对 CPC 中的这一通路一无所知。短的 术语目标是了解 Fn-a5pi-FAK-Pim-1 通路在病理条件下 CPC 中的重要性 条件并推断出一种创新的治疗方法来设计细胞外环境 增强受损心肌的再生和修复。将利用以下方式探索转化潜力 腺相关病毒 9 型 (AAV9) 载体，表达功能性胶原蛋白束缚的 Fn 片段 增强 CPC 的存活、增殖、招募和植入。我们的具体目标是： 1) Fn-a5(31- FAK-Pim-1 信号轴在体内心肌病损伤后被触发，2) a5(31-整合素受体) Fn 激活可通过 FAK-Pim-1 诱导立即应激反应、存活和增殖 CPC 中的信号传导，3) 稳健且持久的 CPC 依赖性再生是通过过度表达介导的 由心肌 AAV9 载体传递的胶原蛋白结合 Fn 片段。意义在于定义有益的 损伤反应的内源性修复方面。长期目标是翻译 Fn 片段 将AAV9方案表达到临床应用，建立再生医学的创新疗法。 相关性（参见说明）： 心脏病，特别是心力衰竭是美国的一个主要公共卫生问题，在美国有相当大的影响。 医疗保健系统的负担。尽管最近在了解病理生理学方面取得了进展，但心脏 失败的五年死亡率仍与大多数癌症相当。该提案的重点是了解如何 受损心脏的环境会影响细胞和分子的修复和再生 等级。