Notch is an evolutionary, conserved, cell–cell signaling pathway that is central to several biological processes, from tissue morphogenesis to homeostasis. It is therefore not surprising that several genetic mutations of Notch components cause inherited human diseases, especially cardiovascular disorders. Despite numerous efforts, current in vivo models are still insufficient to unravel the underlying mechanisms of these pathologies, hindering the development of utmost needed medical therapies. In this perspective review, we discuss the limitations of current murine models and outline how the combination of microphysiological systems (MPSs) and targeted computational models can lead to breakthroughs in this field. In particular, while MPSs enable the experimentation on human cells in controlled and physiological environments, in silico models can provide a versatile tool to translate the in vitro findings to the more complex in vivo setting. As a showcase example, we focus on Notch-related cardiovascular diseases, such as Alagille syndrome, Adams–Oliver syndrome, and cerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy (CADASIL).

中文翻译：

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破译遗传性Notch心血管疾病分子机制的离体模型


Notch 是一种进化的、保守的细胞间信号通路，对于从组织形态发生到体内平衡等多种生物过程至关重要。因此，Notch 成分的几种基因突变导致遗传性人类疾病，特别是心血管疾病也就不足为奇了。尽管付出了很多努力，当前的体内模型仍然不足以揭示这些病理学的潜在机制，阻碍了最需要的医学疗法的发展。在这篇综述中，我们讨论了当前小鼠模型的局限性，并概述了微生理系统（MPS）和目标计算模型的结合如何能够在该领域取得突破。特别是，虽然 MPS 能够在受控的生理环境中对人体细胞进行实验，但计算机模型可以提供一种多功能工具，将体外发现转化为更复杂的体内环境。作为一个展示示例，我们重点关注与 Notch 相关的心血管疾病，例如阿拉吉尔综合征、亚当斯-奥利弗综合征和伴有皮质下梗塞和白质脑病的常染色体显性遗传性脑动脉病 (CADASIL)。