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: 8452811
• 负责人: MARK ALAN SUSSMAN
• 金额: $ 15.92万
• 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
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/8452811
• 关键词: Adoptive Transfer; Adult; 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; Healed; Healthcare Systems; Heart; Heart Diseases; Heart Hypertrophy; Heart failure; Hypertrophy; Immediate-Early Genes; Immunoblotting; Immunohistochemistry; In Vitro; Infarction; Inhibition of Apoptosis; Injury; Innovative Therapy; Integrins; JUN gene; Maintenance; Malignant Neoplasms; Mediating; Mitogen-Activated Protein Kinases; Modeling; Modification; Molecular; Myocardial; Myocardial Infarction; Myocardium; Natural regeneration; Oxidative Stress; Participant; Pathway interactions; Performance; Phosphorylation; Phosphotransferases; Principal Investigator; Public Health; Receptor Activation; Regenerative Medicine; Regimen; Regulation; Research; Resistance; Reverse Transcriptase Polymerase Chain Reaction; Role; Signal Transduction; Starvation; Stem cells; Techniques; Therapeutic; Therapeutic Intervention; Tissues; Translating; United States; base; biological adaptation to stress; c-myc Genes; cardiac repair; cell growth; cellular engineering; clinical application; expectation; extracellular; gene induction; healing; heart disease education; improved; in vivo; innovation; mortality; mouse model; novel; overexpression; pathological aging; programs; receptor expression; repaired; response; response to injury; restoration; 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. ,

在成年人心脏中发现心脏祖细胞（CPC），使人们对新的心脏祖细胞（CPC）有了更高的期望。 心脏病的治疗。然而，CPC的过继转移仅导致暂时的改善， 心脏性能，因为大多数捐献的细胞不能在缺血性瘢痕的不利环境中持续存在。而 方法集中于增强干细胞的能力，受损心肌的工程化是一种 有效的替代策略，以增强心肌修复和再生。细胞外基质（ECM）蛋白 是维持细胞功能的心肌环境的关键成分。的 该提案的总体目标是改善CPC的生存，增殖，招募和持久性， 通过纤连蛋白（Fn）表达的修饰损伤心肌，Fn是一种ECM蛋白， 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-a5 pi-FAK- Pim-1信号级联调节CPC生长和存活。Fn、aSpi、FAK和Pim-1在脑梗死中的相关性研究 心肌细胞生物学是公认的，然而，对CPC中的该途径一无所知。短 长期目标是了解病理条件下CPCs中Fn-a5 pi-FAK-Pim-1通路的意义。 条件和外推一种创新的治疗方法，工程细胞外环境的 受损的心肌，以增强再生和修复。翻译潜力将使用 表达功能性胶原蛋白束缚的Fn片段的9型腺相关病毒（AAV 9）载体， 增强CPC存活、增殖、募集和植入。我们的具体目标是：1）Fn-a5（31- FAK-Pim-1信号传导轴在体内心肌病损伤后被触发，2）α 5 β 1-整联蛋白受体 Fn激活通过FAK-Pim-1诱导即刻应激反应、存活和增殖 3）稳健和持久的CPC依赖性再生是由 由亲心性AAV 9载体递送的胶原结合Fn片段。重要性是定义有益的 内源性修复对损伤反应的方面。长期目标是翻译Fn片段 表达AAV 9方案用于临床应用，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， 对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5年死亡率仍然可以与大多数癌症相媲美。本建议的重点是了解如何 受损心脏的环境可以影响细胞和分子的修复和再生， 水平,