跨模型系统的功能性分析表明,核糖体蛋白在与低可塑性左心综合征相关的生长和增殖缺陷中的作用
Tanja Nielsen1,2, Anaïs Kervadec1, Jeanne L Theis3
1Center for Cardiovascular and Muscular Diseases, Sanford Burnham Prebys Medical Discovery Institute, 10901 North Torrey Pines Road, La Jolla, CA, 92037, USA.
medRxiv : the preprint server for health sciences
|November 24, 2025
概括
核糖体蛋白基因对心脏发育至关重要,可能导致左心脏低可塑性综合征 (HLHS). 这项研究确定了影响心肌细胞增殖的RP基因,并通过遗传和功能分析将其与HLHS病原体联系起来.
科学领域:
- 心血管生物学 心血管生物学
- 遗传学 遗传学 是一个
- 发展生物学 发展生物学
背景情况:
- 缺血性左心综合征 (HLHS) 是一种严重的先天性心脏病 (CHD),其病因不明.
- HLHS的遗传复杂性阻碍了致病基因的识别.
研究的目的:
- 使用全基因组siRNA屏幕识别调节心肌细胞增殖的基因.
- 为了研究核糖体蛋白 (RP) 基因在HLHS病变发生中的作用.
主要方法:
- 人类iPSC衍生的心肌细胞 (hPSC-CMs) 的全基因组siRNA屏幕,以识别增殖调节剂.
- 在HLHS患者队列中进行全基因组测序和罕见变异过.
- 在hPSC-CMs,Drosophila和斑马鱼模型中进行功能验证.
- 用已知的心脏发育基因和通路分析进行遗传相互作用研究 (p53,Hippo/YAP).
主要成果:
- 核糖体蛋白 (RP) 基因被确定为心肌细胞增殖的关键调节者.
- 在HLHS患者中,RP基因的罕见变异被丰富.
- 在各种模型系统中,对RP基因的淘汰会影响心脏生长,引起心脏形或导致致死.
- RP基因与核心心脏转录因子相互作用,并由p53和Hippo通路调节.
结论:
- 在心脏发生过程中,RP基因起着新而至关重要的作用.
- RP基因代表了一个新兴的候选基因类别,涉及到HLHS病变发生.
- 由于RP基因功能障碍导致心肌细胞增殖受损可能会导致HLHS中低可塑性表型.
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