HSF1对重型再生障碍性贫血模型小鼠TNF-β及Fas/Fasl的作用：一个潜在的“偶联”靶点

severe aplastic anemia (SAA) of "heart and kidney" in traditional Chinese medicine clinical symptoms are common, the use of "heart and kidney homologous" method in the treatment of SAA has good curative effect. Modern medical think that the pathogenesis of SAA are associated with TNF-alpha and Fas/Fasl, and that they have pathophysiological basis of common.TNF-alpha by Fas/FasL initiates apoptosis resulting in reduced hematopoietic stem cell. And HSF1 regulates TNF-alpha and Fas/Fasl.Because their same similarity receptor and molecular structure between TNF-alpha and TNF-beta make their similar biological effects .Therefore, we infer that HSF1 is "coupling target" of TNF-beta and Fas/Fasl,influenceing the occurrence of SAA .Here,this topic will make the predicted promoter region and use technical means of protein and molecular biology to explore the changes of expression HSF1 bridge in TNF- beta and Fas/Fasl through Tetramethylpyrazine on treatment of SAA mice in that provide further experimental evidence on SAA "heart kidney homologous"for clinical treatment.

重型再生障碍性贫血（SAA）临床中常见“心肾虚”症状表现，中医运用“心肾同源”法治疗SAA取得了较好的临床疗效。现代医学观察到SAA患者的发病机制与TNF-α及Fas/Fasl有关，并且认为两者可能存在共同的病理生理基础。TNF-α通过Fas/FasL启动凋亡，引起造血干细胞减少。而HSF1对TNF-α、Fas/Fasl均有调控作用。由于TNF-α和TNF-β两者分子结构的相似性和受体的同一性使得两者的生物学作用极为相似，因此，推论认为HSF1是TNF-β及Fas/Fasl两者“偶联的靶点”，通过调控两者的表达而影响SAA的发生。故本课题拟通过预测启动子区域，采用蛋白质及分子生物学技术手段来探讨中药川芎嗪对HSF1桥梁于TNF-β及Fas/Fasl两者的表达变化，进一步为SAA“心肾同源”临床治疗提供实验证据。

重型再生障碍性贫血(SAA)作为一种尚未发现特异性自身抗原的自身免疫性骨髓衰竭疾病，其骨髓微环境存在异常。免疫介导的骨髓衰竭（BMF）小鼠模型是最接近SAA患者发病机制的动物模型。川芎嗪（TMP）作为中药川芎的活性成分之一，能促进骨髓损伤后微环境和造血功能重建，并能减轻辐射诱导的DNA损伤、氧化应激反应及细胞凋亡，而川芎嗪是否能促进BMF模型小鼠骨髓损伤后修复还未见报道。故我们拟采用病理学及分子生物学技术来探索在川芎嗪是否能改善BMF模型小鼠骨髓微环境，并进一步阐述川芎嗪“祛瘀生新”的功效，从而为SAA发病机制的探讨和新药的开发提供思路。通过对X射线和输注淋巴细胞剂量的探索，我们成功地建立了适合SAA实验研究的动物模型即免疫介导的骨髓衰竭（BMF)小鼠模型。体内实验，通过川芎嗪干预BMF小鼠，发现模型小鼠外周血红细胞上升，骨髓病理损伤和充血程度减轻，并且骨髓有核细胞数目增多，说明川芎嗪能改善骨髓微环境，并且进一步阐述了“祛瘀生新”的理论；川芎嗪干预后肾脏病理减轻，并且氧化氧化应激指标下降，说明川芎嗪具有肾脏保护作用。体外实验，通过流式分选BMF小鼠骨髓CD8+T细胞，并用川芎嗪进行干预，发现川芎嗪能抑制T活化后增殖。

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