Department of Molecular Biology, Hamon Center for Regenerative Science and Medicine, University of Texas Southwestern Medical Center, Dallas.
Circ Res. 2022 Jun 10;130(12):1827-1850. doi: 10.1161/CIRCRESAHA.122.320496. Epub 2022 Jun 9.
Cardiovascular disease remains the leading cause of morbidity and mortality in the developed world. In recent decades, extraordinary effort has been devoted to defining the molecular and pathophysiological characteristics of the diseased heart and vasculature. Mouse models have been especially powerful in illuminating the complex signaling pathways, genetic and epigenetic regulatory circuits, and multicellular interactions that underlie cardiovascular disease. The advent of CRISPR genome editing has ushered in a new era of cardiovascular research and possibilities for genetic correction of disease. Next-generation sequencing technologies have greatly accelerated the identification of disease-causing mutations, and advances in gene editing have enabled the rapid modeling of these mutations in mice and patient-derived induced pluripotent stem cells. The ability to correct the genetic drivers of cardiovascular disease through delivery of gene editing components in vivo, while still facing challenges, represents an exciting therapeutic frontier. In this review, we provide an overview of cardiovascular disease mechanisms and the potential applications of CRISPR genome editing for disease modeling and correction. We also discuss the extent to which mice can faithfully model cardiovascular disease and the opportunities and challenges that lie ahead.
心血管疾病仍然是发达国家发病率和死亡率的主要原因。近几十年来，人们投入了非凡的努力来定义患病心脏和血管的分子和病理生理学特征。小鼠模型在阐明心血管疾病的复杂信号通路、遗传和表观遗传调控回路以及多细胞相互作用方面特别有力。CRISPR 基因组编辑的出现开创了心血管研究的新纪元，也为疾病的基因矫正带来了可能。下一代测序技术极大地加速了致病突变的鉴定，而基因编辑的进步使得在小鼠和患者来源的诱导多能干细胞中快速模拟这些突变成为可能。通过在体内递送基因编辑组件来纠正心血管疾病的遗传驱动因素，尽管仍然面临挑战，但这代表了一个令人兴奋的治疗前沿。在这篇综述中，我们概述了心血管疾病的机制以及 CRISPR 基因组编辑在疾病建模和矫正方面的潜在应用。我们还讨论了小鼠在多大程度上可以真实地模拟心血管疾病，以及未来的机遇和挑战。
