COLLABORATIVE R01

描述 (改编自申请人的摘要)适用于 心力衰竭患者，心脏移植除外， 未能解决心肌细胞数量不足的问题 这些人中的许多人的心脏功能都会受到影响。一个 成功的生物技术策略将新的心肌细胞添加到 受损的心脏将满足主要的临床需求。调查人员建议 鉴定或设计心脏来源的细胞，在移植到 心肌壁，能够增殖、分化和 以足以改善心脏功能的方式纠正图案形成 功能。该方法新颖、系统和多学科，并将 建立在不断扩大的关于以下方面的新知识的基础上 哺乳动物和两栖类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和 强大的模型系统。参与调查的人员具有以下专业知识 与这项研究相关的多个科学领域，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 在单一机构内工作，这项联合提案通过以下方式得到加强 预先存在的和正在进行的科学关系。调查人员 建议同时对生物学有更详细的了解 骨骼肌源性干细胞(卫星细胞)及其与 来自发育中心脏的肌源性前体细胞(成心细胞)， 特别是在组织再生的背景下。推定为心源性 细胞将从早期胚胎或拟胚体中分离出来 培养，或通过骨骼肌源性细胞的转分化进行工程。 每种候选单元格类型都将在以下方面进行全面表征 它的表达基因及其促进有效表达的能力 异位移植后的心源性组织修复 或进入心肌病动物的心肌壁。每一轮 测试之后将应用增强策略，选择 根据之前在每个 该提案的各个组成部分，旨在优化组织 修复过程。通过这种迭代的方式，调查人员希望获得 最终将促进细胞发育的知识 促进人类患者心肌修复的移植策略 患有心力衰竭的。

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.