脱离X染色体不活化的基因调节膜肌纤维细胞中的性别差异
Brian A Aguado1,2,3,4, Cierra J Walker5,6, Joseph C Grim1,2
1Department of Chemical and Biological Engineering (B.A.A., J.C.G., B.J.V., A.G.R., K.S.A.), University of Colorado, Boulder.
Circulation
|January 10, 2022
概括
大动脉狭窄的性别差异涉及不同的分子途径. 脱离X染色体不活化的基因有助于女性肌纤维细胞的活化,影响疾病的进展.
科学领域:
- 心血管生物学
- 生物材料科学
- 遗传学
背景情况:
- 大动脉狭窄表现为性双形,在女性 (纤维化) 和男性 (化) 中具有明显的病理特征.
- 驱动这些性别特异性的潜在细胞内分子机制尚不清楚.
研究的目的:
- 研究间细胞 (VIC) 激活和失活的性别特异性分子机制.
- 使用一种新的水凝生物材料培养系统来建模微环境,并研究性别依赖的VIC反应.
主要方法:
- 开发了水凝生物材料来培养性别特定的VIC并模仿门微环境.
- 使用RNA测序来识别涉及性取决于VIC激活的途径.
- 使用小分子抑制剂和siRNA来阐明性特异性细胞对微环境线索的反应机制.
主要成果:
- 与男性VIC相比,女性VIC表现出更高的α-平滑肌肉动蛋白 (α- SMA) 应激纤维,并增加了对矩阵度的反应.
- 转录组分析发现Rho相关蛋白激酶 (ROCK) 信号是依性肌纤维细胞激活的关键驱动因素.
- 发现逃脱X染色体失活的基因,如BMX和STS,通过ROCK信号来部分调节女性肌纤维细胞活化.
结论:
- 在体外和体内证实了性别相关的肌纤维细胞激活途径.
- 脱离X染色体不活化的基因在大动脉缩进展中的性别差异中起作用.
- 将性别视为一种生物变量对于了解疾病机制和开发基于性别的精确疗法至关重要.
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