Harnessing endothelial cell transdifferentiation for cardiovascular therapy

心血管疾病是导致死亡的主要原因，因此最近的努力集中在使用 治疗心脏和血管病变的新兴基因技术。这些努力主要是 基于越来越多的研究，包括我们的初步数据，观察到转基因 通过静脉注射病毒载体传递到心肌细胞。然而，到目前为止，还没有 这一重要发现背后的任何机制都得到了经验上的支持。我的实验室专注于 多年来内皮细胞转分化的前景和积累的证据表明 这一过程存在于成年小鼠体内，可能与不同细胞类型的动态平衡有关。我们的 初步数据和我们建议的方法将决定心肌细胞标记 是转分化事件(内皮细胞或其他)的结果，还是细胞外的产物 囊泡转移。这项工作还将确认这种标记的来源是否是内皮细胞。我们 也有兴趣确定静脉注射转基因到其他细胞类型的性质，这些细胞 可以提供关于内皮细胞转分化为离散壁龛的定位的信息。 这些小生境的存在可能对加强血管病理学有重要的意义。 这些地区。这项工作将使用单独的最先进的细胞谱系追踪进行 包括病毒、蛋白质和基于细胞的方法的策略。这项研究提供的答案 将有助于指导心脏基因治疗的努力，增进我们对内皮细胞生物学的理解， 并为心血管疾病提供了潜在的新见解。

Cardiovascular disease is the leading cause of death, so recent efforts have focused on using emerging genetic technologies to remediate cardiac and vascular pathologies. These efforts are largely based on a growing number of studies, including our preliminary data, that have observed transgene delivery to cardiac myocytes via intravenous injection of a viral vector. However, to date, there is no empirically backed rationale for any mechanism underlying this important finding. My lab has focused on the prospect of endothelial cell transdifferentiation for many years and accrued evidence that this process exists in adult mice and may be responsible for the homeostasis of diverse cell types. Our preliminary data coupled with our proposed approach will determine whether cardiac myocyte labeling is the result of a transdifferentiation event (endothelial cell or otherwise) or the product of extracellular vesicle transfer. This work will also confirm whether the source of this labeling is endothelial cells. We are also interested in determining the nature of intravenous transgene delivery to other cell types, which could yield information about the localization of endothelial cell transdifferentiation to discrete niches. The existence of such niches could have important implications for enhancing the vascular pathology of those regions. This work will be undertaken using separate state-of-the-art cell lineage tracing strategies that encompass virus, protein, and cell-based methods. The answers provided by this study will help guide efforts for cardiac genetic therapy, advance our understanding of endothelial cell biology, and provide potentially new insights into cardiovascular disease.