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PPAR-α和葡萄糖皮质体受体协同作用,促进红色素原体的自我更新

Hsiang-Ying Lee¹, Xiaofei Gao¹, M Inmaculada Barrasa¹

¹Whitehead Institute for Biomedical Research, Nine Cambridge Center, Cambridge, Massachusetts 02142, USA.

|May 14, 2015

概括

过氧体增殖器激活受体α (PPAR-α) 激动剂,当与葡萄糖皮质类药物结合时,通过刺激早期的祖先细胞来增强红细胞的产生. 这种组合显示出治疗抗红色素耐药性贫血症的前景.

科学领域:

血液学血液学血液学
分子生物学分子生物学
药理学药理学是指药理学的学科.

背景情况:

由于缺少或不敏感的红色素原生细胞 (CFU-Es),许多贫血症对红色素素 (Epo) 具有抗性.
有效的治疗需要刺激早期红细胞形成阶段的药物,增强对Epo敏感的原始细胞的产生.
葡萄糖皮质类药物以前被证明可以刺激早期红色素原体 (BFU-Es) 的自我更新,并增加红细胞的产生.

研究的目的:

为了研究是否氧酶增殖器激活受体α (PPAR-α) 激活与葡萄糖皮质体受体 (GR) 信号交互.
确定这种协同作用是否增强早期红色素原体 (BFU-Es) 和红细胞生产的自我更新.
评估PPAR-α激动剂在抗红素性贫血模型中的治疗潜力.

主要方法:

同时治疗小鼠胎儿肝脏BFU-Es和人类CD34(+) 外周血液前体与PPAR-α激动剂 (GW7647,纤维酸) 和葡萄皮质皮质激素.
使用人类细胞的新型培养系统评估BFU-E自我更新和成熟红细胞的产生.
在体内研究使用野生类型和Ppara(-/-) 鼠标来评估因氨酸诱导的血液溶解性贫血和慢性贫血模型的恢复.
染色体免疫沉测序 (ChIP-seq) 用于分析PPAR-α和GR在染色体位点的同时占用.

主要成果:

PPAR-α激动剂与葡萄皮质类药物协同作用,显著促进BFU-E自我更新,并在小鼠和人类细胞培养物中增加成熟红细胞的产生.
在野生型小鼠中,PPAR-α激动剂有助于从急性血液溶解性贫血中恢复,但在Ppara(-/-) 小鼠中没有,这表明PPAR-α的作用.
在慢性贫血的小鼠模型中,PPAR-α激动剂也减轻了贫血.
发现PPAR-α和GR共同占据色素位点,在激素激活时PPAR-α被招募到GR相邻的位点.

结论:

PPAR-α的激活与葡萄糖皮质体受体信号协同作用,以增强早期红色素原体的自我更新和红细胞的产生.
PPAR-α在红色素形成中起着至关重要的作用,特别是在血液溶解性贫血的恢复中.
经过临床测试的PPAR-α激动剂可以提高皮质类固醇治疗Epo耐药性贫血的疗效.

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