COLLABORATIVE R01

描述 （改编自申请人摘要）目前的治疗方法适用于 心力衰竭患者，除心脏移植外， 未能解决心肌细胞的数量不足， 损害了许多人的心室性能。 一 成功的生物技术策略，增加新的心肌细胞， 受损的心脏可以满足主要的临床需求 研究人员建议， 鉴定或改造心源性细胞， 心肌壁，能够增殖，分化， 以足以改善心脏功能的方式形成正确的模式 功能 该方法新颖、系统、多学科， 建立在不断扩大的新知识基础上， 哺乳动物和两栖动物胚胎心脏发生的分子机制， 以及成人骨骼肌的肌源性修复。 实验计划 旨在最大限度地利用新兴技术， 强大的模型系统。 参与的研究者具有以下方面的专业知识： 与这项研究相关的不同科学领域，包括生物物理学， 发育生物学，分子遗传学和临床心脏病学，但他们 在一个单一的机构内开展工作，这一联合提案得到了加强， 现有的和正在进行的科学关系。 调查人员 同时，我也想更详细地了解 骨骼肌源性干细胞（卫星细胞），以及它们与 来自发育中的心脏的肌原性前体细胞（成心细胞）， 特别是在组织再生的背景下。 推定心源性 细胞将从早期胚胎或从胚状体中分离， 培养或通过骨骼肌原性细胞的转分化工程化。 每种候选细胞类型将在以下方面进行全面表征： 它的表达基因库，以及它促进有效的 异位部位移植后的心源性组织修复 或进入心肌病动物的心肌壁。 每轮 测试之后将应用增强战略，选择 根据在每一个区域内从先前分析获得的结果， 该提案的单独组件，旨在优化组织 修复过程。 通过这种迭代方式，研究人员希望获得 这些知识最终将促进细胞的发育， 促进人类患者心肌修复的移植策略 患有心力衰竭

DESCRIPTION (Adapted from the applicant's abstract) Current therapeutics applied to patients with heart failure, with the exception of cardiac transplantation, fail to address the quantitative deficiency of cardiomyocytes that compromises ventricular performance in many of these individuals. A successful biotechnological strategy to add new cardiomyocytes to the damaged heart would meet a major clinical need. The investigators propose to identify or engineer cardiogenic cells that, following transplantation to the myocardial wall, are capable of proliferation, differentiation, and correct pattern formation in a manner sufficient to improve cardiac function. The approach is novel, systematic and multidisciplinary, and will be constructed upon an expanding foundation of new knowledge concerning molecular mechanisms of cardiogenesis in mammalian and amphibian embryos, and of myogenic repair in adult skeletal muscles. The experimental plans have been designed to take maximum advantage of emerging technologies and powerful model systems. The participating investigators have expertise in diverse areas of science relevant to this research including biophysics, developmental biology, molecular genetics, and clinical cardiology, but they work within a single institution and this joint proposal is enhanced by pre-existing and ongoing scientific relationships. The investigators propose to gain, in parallel, a more detailed understanding of the biology of skeletal myogenic stem cells (satellite cells) and how they contrast with myogenic precursor cells (cardioblasts) from the developing heart, specifically in the context of tissue regeneration. Putative cardiogenic cells will be isolated from early embryos or from embryoid bodies in culture, or engineered by transdifferentiation of skeletal myogenic cells. Each candidate cell type will be characterized comprehensively with respect to its repertoire of expressed genes, and its capacity to promote effective cardiogenic tissue repair following transplantation into ectopic locations or into the myocardial wall of cardiomyopathic animals. Each round of testing will be followed by the application of enhancing strategies, chosen on the basis of results acquired from preceding analyses within each of the separate components of this proposal, and designed to optimize the tissue repair process. In this iterative manner, the investigators expect to gain knowledge that ultimately will foster the development of cell transplantation strategies to promote myocardial repair in human patients afflicted with heart failure.