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Nature:靶向核受体分子 治疗贫血新策略

放大字体  缩小字体 发布日期:2015-06-01  浏览次数:265
核心提示:2015年5月18日讯 /生物谷BIOON/ --近日,来自美国麻省理工学院的研究人员在著名国际学术期刊nature在线发表了一项最新研究进展,他们发现PPARa激动剂对于治疗红细胞生成素抵抗性贫血症具

2015年5月18日讯 /生物谷BIOON/ --近日,来自美国麻省理工学院的研究人员在著名国际学术期刊nature在线发表了一项最新研究进展,他们发现PPARa激动剂对于治疗红细胞生成素抵抗性贫血症具有重要作用。许多急性和慢性贫血症,包括红细胞溶解,脓毒病以及遗传性骨髓衰竭如Diamond-Blackfan贫血,对于红细胞生成素(Epo)治疗并不能获得比较好的治疗效果,其中的原因主要是由于响应Epo处理的克隆形成单元红系祖细胞(CFU-E)数目过少或对与Epo处理不够敏感,不足以维持红细胞产生。对这些贫血病的治疗需要一种能够作用于红细胞形成早期阶段的药物,增强Epo敏感性的CFU-E祖细胞形成。在之前一项研究中,研究人员证明糖皮质激素能够特异性刺激一种早期红系祖细胞--BFU-E的自我更新,从而增加终末分化的红细胞的产生。而在该项研究中,研究人员发现利用PPARa激动剂GW7647和菲诺贝特激活PPARa能够与糖皮质激素受体协同促进BFU-E的自我更新。经过一段时间处理,这些激动剂能够大大增加成熟红细胞的产生。虽然PPARa敲除小鼠并没有表现出造血功能的变化,但利用PPARa激动剂处理PPARa敲除小鼠并不能恢复苯肼诱导的急性溶血性贫血,而野生型小鼠可以得到恢复。研究人员利用BFU-E细胞进行机制研究,发现PPARa能够与糖皮质激素受体共同占据部分染色质的转录因子结合位点,利用PPARa激动剂进行处理会促使更多的PPARa募集到糖皮质激素受体临近为止,促进糖皮质激素受体依赖性的BFU-E 自我更新。这项研究发现PPARa激动剂在刺激早期红系祖细胞自我更新方面具有重要作用,表明PPARa激动剂可能会提高皮质甾醇在治疗Epo抵抗性贫血症方面的治疗效果,因此这项研究具有重要意义。(生物谷Bioon.com)本文系生物谷原创编译整理。欢迎转载!转载请注明来源并附原文链接。更多资讯请下载生物谷资讯APPdoi:10.1038/nature14326PPAR-α and glucocorticoid receptor synergize to promote erythroid progenitor self-renewalHsiang-Ying Lee,Xiaofei Gao,M. Inmaculada Barrasa,Hu Li,Russell R. Elmes,Luanne L. Peters & Harvey F. LodishMany acute and chronic anaemias, including haemolysis, sepsis and genetic bone marrow failure diseases such as Diamond-Blackfan anaemia, are not treatable with erythropoietin (Epo), because the colony-forming unit erythroid progenitors (CFU-Es) that respond to Epo are either too few in number or are not sensitive enough to Epo to maintain sufficient red blood cell production1, 2, 3, 4, 5,6, 7, 8, 9. Treatment of these anaemias requires a drug that acts at an earlier stage of red cell formation and enhances the formation of Epo-sensitive CFU-E progenitors. Recently, we showed that glucocorticoids specifically stimulate self-renewal of an early erythroid progenitor, burst-forming unit erythroid (BFU-E), and increase the production of terminally differentiated erythroid cells10, 11. Here we show that activation of the peroxisome proliferator-activated receptor α (PPAR-α) by the PPAR-α agonists GW7647 and fenofibrate synergizes with the glucocorticoid receptor (GR) to promote BFU-E self-renewal. Over time these agonists greatly increase production of mature red blood cells in cultures of both mouse fetal liver BFU-Es and mobilized human adult CD34+peripheral blood progenitors, with a new and effective culture system being used for the human cells that generates normal enucleated reticulocytes. Although Ppara?/? mice show no haematological difference from wild-type mice in both normal and phenylhydrazine (PHZ)-induced stress erythropoiesis, PPAR-α agonists facilitate recovery of wild-type but not Ppara?/? mice from PHZ-induced acute haemolytic anaemia. We also show that PPAR-α alleviates anaemia in a mouse model of chronic anaemia. Finally, both in control and corticosteroid-treated BFU-E cells, PPAR-αco-occupies many chromatin sites with GR; when activated by PPAR-α agonists, additional PPAR-αis recruited to GR-adjacent sites and presumably facilitates GR-dependent BFU-E self-renewal. Our discovery of the role of PPAR-α agonists in stimulating self-renewal of early erythroid progenitor cells suggests that the clinically tested PPAR-α agonists we used may improve the efficacy of corticosteroids in treating Epo-resistant anaemias.

 
 
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