Closed-Chest Cell Injections into Mouse Myocardium Targeted by Ultrasound

描述（由申请人提供）：心肌内细胞植入和治疗基因注射已被提议作为缺血性心脏病的治疗方法。然而，最近的文献包含了许多相互矛盾的结果。不同的研究小组将相同的细胞群注入小鼠心脏，并报告了不同的发现，从心脏功能的改善到缺乏改善和缺乏分化的干细胞。该建议旨在评估以下假设：这些矛盾部分源于注射到心肌壁而不是左心室腔的不同成功率，并且高分辨率超声心动图的非侵入性成像可以准确地靶向注射到正常和梗死小鼠心脏，提供临床相关系统，用于研究潜在的细胞植入和基因治疗。首先，将注射超声心动图造影剂和荧光微球的混合物，以将超声引导注射期间观察到的针位置与组织学检查证明的实际注射部位相关联。在系统优化后，高分辨率超声心动图将用于引导标记细胞经胸植入手术梗死小鼠的心脏，靶向梗死边缘区并证明概念验证。该系统将用于研究标记的骨髓来源的细胞通过心肌迁移到受损组织的能力，通过靶向注射混合有不同大小和颜色的荧光微球的标记细胞。它还将用于比较梗死手术期间心肌内细胞植入与梗死后几天植入的效果，这是一种临床相关性更高的模型，在没有超声引导的情况下很难实现;以及多次植入。这将导致进一步的研究，有针对性地注射到梗死边缘区的骨髓来源的细胞和成肌细胞表达的生长因子。相关性：植入所谓的成体干细胞和注射编码生长因子的基因是治疗心脏病发作幸存者心脏功能不良的潜在方法。许多实验可以在小鼠身上进行;然而，它们的心脏太小，很难以临床相关的方式注射到它们体内。这项研究将使用高分辨率超声引导这种注射进入小鼠心脏，而无需手术，并将使小鼠成为此类实验的更好模型。

DESCRIPTION (provided by applicant): Intramyocardial cell implantation and injection of therapeutic genes have been proposed as therapies for ischemic heart disease. However, the recent literature contains numerous contradictory results. Different research groups inject identical cell populations into mouse hearts and report disparate findings, ranging from improvement of cardiac function to lack of improvement and absence of differentiated stem cells. This proposal is designed to evaluate the hypothesis that these contradictions stem, in part, from varying success of injection into the myocardial wall rather than the left ventricular cavity, and that non-invasive imaging with high resolution echocardiography can accurately target injections into normal and infarcted mouse hearts, providing a clinically relevant system with which to study potential cell implantation and gene therapies. First, a mixture of echocardiography contrast agent and fluorescent microspheres will be injected to correlate the observed needle position during echo-guided injections with the actual injection site as evidenced by histological examination. After the system has been optimized, high resolution echocardiography will be used to guide transthoracic implantations of labeled cells into the hearts of surgically infarcted mice, targeting the infarct border zone and demonstrating proof of concept. The system will be used to study the ability of labeled bone marrow derived cells to migrate through cardiac muscle to damaged tissue by targeted injections of labeled cells mixed with fluorescent microspheres of different sizes and colors. It will also be used to compare the effects of intramyocardial cell implantation during the infarction procedure to implantation several days after infarction, a more clinically relevant model that is very difficult to achieve without echo-guidance; as well as at multiple times. This will lead to further studies of targeted injection into the infarct border zone of both bone marrow-derived cells and myoblasts expressing growth factors. RELEVANCE: The implantation of so-called adult stem cells and the injection of genes encoding growth factors are potential treatments for poor cardiac function that typically plagues heart attack survivors. Many experiments can be carried out in mice; however, their hearts are so small that it is difficult to inject into them in a clinically relevant way. This research will use high-resolution ultrasound to guide such injections into the mouse heart, without surgery, and will make the mouse a much better model for such experiments.