Cardioprotective Repair through Cardiopoiesis

通过心脏生成进行心脏保护修复

• 批准号: 7028113
• 负责人: ANDRE TERZIC
• 金额: $ 37万
• 依托单位: MAYO CLINIC ROCHESTER
• 依托单位国家: 美国
• 财政年份: 2006
• 资助国家: 美国
• 起止时间: 2006-01-01 至 2010-12-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7028113
• 关键词: atomic force microscopy; cardiac myocytes; cardiovascular disorder prevention; cardiovascular disorder therapy; cell differentiation; confocal scanning microscopy; embryonic stem cell; gene expression; genetically modified animals; heart contraction; laboratory mouse; microarray technology; muscle contraction; musculoskeletal regeneration; myocardial infarction; myocardium; pluripotent stem cells; stem cell transplantation

DESCRIPTION (provided by applicant): Myocardial infarction is a leading cause of morbidity with loss of contractile performance precipitated by the limited capacity of heart muscle for self-renewal. The aptitude of embryonic stem cells for differentiation into cardiomyocytes provides an opportunity for regenerative repair. Indeed, the basis for therapeutic use of these quintessential stem cells lies in their inherent pluripotency, yet the distinct ability for multi-lineage differentiation carries the liability of neoplastic growth that outweighs benefit impeding reparative applications. The objective of this proposal is to hone stem cell plasticity in order to nullify malignancy-prone unguided differentiation for safe repair. Preliminary studies demonstrate the aptitude for definitive cardiogenic commitment of an embryonic stem cell population within the developing embryoid body, during a transient window of endoderm-directed cardiotrophic signaling, with the resulting specification of the mesoderm yielding a progenitor "cardiopoietic" stem cell phenotype. Aim #1 will (i) isolate this pro-cardiogenic population utilizing embryoid body-based stem cell differentiation, (ii) define its molecular identity, and (iii) determine its propensity for terminal cardiomyogenic transformation. Aim #2 will (i) decipher the endoderm-derived cardiotrophic signaling, (ii) recruit in an embryoid body-free manner the pro-cardiogenic cardiopoietic population at large scale, and (iii) validate in vivo the safety profile of this novel stem cell type. Aim #3 will (i) assess the curative potential of procured cardiopoietic stem cells in treating myocardial infarction, (ii) determine the underlying mechanism for repair, and (iii) engineer stem cells for augmented tolerance to stress achieving enhanced cardioprotective outcome. Based on the characterization of cardiopoietic stem cells and the profiling of cardiotrophic cues, this proposal will dissect the fundamental process of cardiopoiesis securing formative confinement of pluripotency. Dissection of cardiogenesis at the molecular and cellular level will be further integrated into a therapeutic paradigm, and translated to the organ and organism level for safe cell-based regenerative therapy of myocardial infarction.

描述（由申请人提供）：心肌梗死是一种主要的发病原因，由于心肌自我更新能力有限，导致收缩能力丧失。胚胎干细胞分化为心肌细胞的能力为再生修复提供了机会。事实上，这些典型干细胞的治疗用途的基础在于其固有的多能性，但多谱系分化的独特能力带来了肿瘤生长的可能性，其超过了阻碍修复应用的益处。该提案的目的是磨练干细胞的可塑性，以消除恶性倾向的无指导分化，以实现安全修复。初步研究表明，在发育中的拟胚体内，胚胎干细胞群体在内胚层定向的心肌营养信号传导的短暂窗口期间，具有确定的心源性承诺的能力，所产生的中胚层的特化产生祖细胞“心脏生成”干细胞表型。目标#1将（i）利用基于胚状体的干细胞分化分离这种促心源性群体，（ii）定义其分子身份，以及（iii）确定其终末心肌转化的倾向。目标#2将（i）破译内胚层来源的心肌营养信号传导，（ii）以无胚体的方式大规模招募促心源性心肌生成群体，以及（iii）在体内验证这种新型干细胞类型的安全性。目标#3将（i）评估获得的心脏造血干细胞在治疗心肌梗死中的治疗潜力，（ii）确定修复的潜在机制，以及（iii）工程化干细胞以增强对压力的耐受性，从而实现增强的心脏保护效果。基于对心脏造血干细胞的表征和对心肌营养因子的分析，该建议将剖析心脏造血的基本过程，以确保多能性的形成限制。在分子和细胞水平上对心脏发生的剖析将进一步整合到治疗范式中，并转化为器官和生物体水平，以安全的细胞为基础的心肌梗死再生治疗。