副本数量丢失的 APP 导致胸前大动脉解剖
Qiannan Gao1,2, Minghui Bao3, Jiangshan Tan2
1Beijing Anzhen Hospital of Capital Medical University and Beijing Institute of Heart Lung and Blood Vessel Diseases, Beijing, China.
概括
在 APP 中的副本数变化加速胸前大动脉剖析 (TAD) 的进展. 缺少APP会加剧大动脉损伤并促进TAD,突出显示APP是这种致命疾病的潜在治疗目标和遗传风险因素.
科学领域:
- 心血管研究研究心血管研究
- 遗传学 是一个遗传学.
- 分子生物学分子生物学
背景情况:
- 胸前动脉解剖 (TAD) 是心血管突然死亡的主要原因.
- 在零星TAD中对副本数变异 (CNV) 的研究有限,需要进行大规模研究.
研究的目的:
- 通过使用全基因组测序 (WGS) 在零星TAD中全面调查和功能验证CNV.
- 阐明已识别的基因在体内和体外TAD病原发生中的作用.
主要方法:
- 在257名零星TAD患者和132名对照中进行全基因组测序 (WGS).
- 基因淘汰小鼠模型和体外实验 (RNA-seq,分子生物学).
- 在TAD中分析CNV,基因表达和细胞机制.
主要成果:
- 在TAD.中确定了四个潜在的CNV基因 (DSCAM,APP,LINC00907,PROCR)
- 在TAD患者的大动脉中观察到减少的APP表达.
- 在小鼠模型中,APP缺乏加剧了弹性纤维的碎片化,并促进了TAD的形成,在体外诱导了VSMC亡和分泌表型切换.
结论:
- 这项研究是首次报告TAD中APP的新型CNV.
- APP缺陷加快了TAD的开始和进展.
- APP是一个有前途的治疗标和TAD的潜在遗传风险因素.
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