诺奇3删除调节HIV-1基因表达和全身炎症,以改善慢性脏病
Mackenzie Thornton1,2, Nicole Sommer1,2, Mercedes McGonigle1,2
1Department of Internal Medicine, University of Kansas Medical Center, Kansas City, KS.
bioRxiv : the preprint server for biology
|September 25, 2023
概括
针对Notch3激活显著减少损伤,炎症和HIV-1模型中的死亡率. 这种Notch3抑制为与艾滋病毒相关的脏疾病和潜在的其他与艾滋病毒相关的疾病提供了双重治疗方法.
科学领域:
- 免疫学 免疫学 免疫学
- 病毒学 病毒学
- 腎臟病學 (nephrology) 是一種醫學專業.
背景情况:
- 抗逆转录病毒疗法 (ART) 可以降低HIV-1的发病率,但不能消除潜在的感染,导致慢性炎症和并发症.
- 艾滋病毒-1感染会导致慢性炎症和并发症,包括艾滋病毒相关性病 (HIV-AN).
- 在HIV-1模型和HIV-AN患者的细胞中观察到Notch3信号的激活.
研究的目的:
- 研究针对HIV-1相关慢性病 (HIV-CKD) 的Notch3激活的治疗潜力.
- 确定Notch3抑制是否可以改善HIV-1小鼠模型中的损伤,炎症和死亡率.
主要方法:
- 在HIV-Tg26小鼠 (HIV-Tg-N3KO) 中产生Notch3淘汰 (N3KO).
- 评估HIV-Tg-N3KO小鼠的损伤,皮肤病变和死亡率,与HIV-Tg26对照小鼠相比.
- 在组织上进行大量RNA测序.
- 研究了Notch3和HIV-1促进体相互作用.
- 在骨髓衍生巨细胞 (BMDMs) 中分析了Notch3激活.
- 测量了系统性炎症标志物 (TNF-α,MCP-1).
主要成果:
- 与HIV-Tg26小鼠相比,HIV-Tg-N3KO小鼠的损伤,皮肤病变和死亡率显著降低.
- N3KO降低了脏透细胞的数量,并抑制了HIV基因的表达.
- 发现Notch3的激活促进了HIV-1促进剂的活性,而HIV-1的诱导增加了Notch3的激活,这表明了反循环.
- 在HIV-Tg-N3KO小鼠中,炎症性细胞因子和化学因子的系统水平降低了.
- 从HIV-Tg26小鼠的BMDM中观察到Notch3激活,这表明系统性参与.
结论:
- 向Notch3激活通过减少损伤和病毒基因表达来证明HIV-CKD的双重治疗效果.
- 诺奇3抑制可能是管理HIV-CKD和潜在的其他艾滋病毒相关病理的新策略.
- 在Notch3和HIV-1之间发现的反机制需要进一步研究,以开发治疗方法.
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