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 新兴的基因技术来治疗心脏和血管疾病。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，已经观察到转基因 通过静脉内注射病毒载体递送至心肌细胞。然而，到目前为止，没有 这一重要发现背后的任何机制的经验支持的理由。我的实验室专注于 关于内皮细胞转分化的前景的研究已经进行了很多年，并积累了证据表明， 这一过程存在于成年小鼠中，可能负责不同细胞类型的稳态。我们 初步数据加上我们提出的方法将确定心肌细胞标记是否 是转分化事件（内皮细胞或其他）的结果或细胞外分化的产物。 囊泡转移这项工作也将确认这种标记的来源是否是内皮细胞。我们 也对确定静脉内转基因递送到其他细胞类型的性质感兴趣， 可以产生关于内皮细胞转分化到离散小生境的定位的信息。 这些小生境的存在可能对增强血管病理学有重要意义 这些地区。这项工作将采用单独的国家最先进的细胞谱系追踪 包括病毒，蛋白质和细胞为基础的方法的战略。本研究提供的答案 将有助于指导心脏基因治疗的努力，促进我们对内皮细胞生物学的理解， 并为心血管疾病提供潜在的新见解。

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.