TPO-MPL通路异常在再生障碍性贫血发病中的机制研究

Severe aplastic anemia (SAA) is a life-threatening disease characterized by hypocellular marrow and pancytopenia as a result of reduction in hematopoietic progenitor and stem cells (HSPCs). One third of patients have disease that is refractory to immunosuppression, with persistent, severe cytopenia and a profound deficit in hematopoietic stem cells and progenitor cells. The binding of TPO to Mpl, induces the dimerization of Mpl. This allows the associatedJanus Kinase 2 (Jak2) molecules to transphosphorylate, leading to their activation. Activated Jak2 then phosphorylates Stat3 and Stat5,which also contribute to the negative regulation of TPOsignaling by upregulating expression of members of the SOCS(suppressors of cytokine signaling) family . Previously, we found that SOCS1 is upregulated in patients. Therefore, we postulate that TPO signaling could be reduced by IFNɣ. In order to profile crosstalk of these two pathways, RNA-seq PCR Array and flow cytometry will be used for detecting transcriptome and phosphoprotein expression difference. HSC function will be evaluated through colony-forming unit assay (CFU assay), cell cycle, apoptosis, BrdU assay and NOD-SCID mice transplantation. Our findings may uncover an unknown mechanisms regulating TPO-MPL pathway and may provide an alternative method for relapse/refractory AA patients.

重型再生障碍性贫血（SAA）是危及生命的骨髓衰竭性疾病。探讨其造血干细胞衰竭（HSC）的机制对重建造血有重要意义。TPO-MPL通路在调节HSC自我更新中发挥重要作用，JAK2是TPO-MPL信号转导途径活化的关键激酶之一，细胞因子信号转导抑制子-1(SOCS-1) 可直接或者间接抑制JAK2激酶的活性。前期研究发现SAA患者血浆TPO水平和CD34+细胞中SOCS-1转录水平显著升高，提示TPO-MPL通路细胞信号传导受阻。本课题拟在既往研究的基础上，通过PCR Array、流式细胞术（FACS）、序贯移植实验等方法从分子、细胞和整体水平探讨TPO-MPL对HSC功能的影响，初步阐明TPO-MPL调控HSC分子机制，为复发难治性SAA的治疗提供新的思路和依据。

据报道，促炎细胞因子干扰素γ（IFNγ）可抑制造血。IFNγ介导人造血干细胞和祖细胞（HSPC）耗竭的机制尚不完全清楚。我们发现，IFNγ与血小板生成素（TPO）特异性形成异聚体，后者是HSPC生存的主要正调节因子，通过阻断低亲和力结合位点，干扰TPO诱导的信号通路，导致TPO与其受体的结合功能收到抑制。Eltrombopag是一种TPO小分子类似物，与TPO不同，其与受体的结合不会被IFNγ所干扰。细胞因子异聚物的形成是一个以前未被认识的机制，通过它，IFNγ损伤HSPC；这一新的理解可能对其他慢性炎症疾病有治疗意义。

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