TNFAIP8在急性髓性白血病耐药中的作用及机制研究

项目名称： TNFAIP8在急性髓性白血病耐药中的作用及机制研究

项目编号： No.81500130

项目类型： 青年科学基金项目

立项/批准年度： 2016

项目学科： 医药、卫生

项目作者： 卢菲

作者单位： 山东大学

项目金额： 18万元

中文摘要： 多药耐药（MDR）是急性髓性白血病(AML)难治/复发的重要原因，也是制约AML治疗的瓶颈。因此探寻MDR的调控机制，寻找有效靶点是目前难治与复发AML治疗的关键点。新近研究发现TNFAIP8对细胞凋亡具有负性调节作用，在肿瘤发生、发展及侵袭过程发挥重要作用。我们前期研究发现TNFAIP8与AML耐药过程密切相关，然而其在AML耐药中发挥作用的途径及机制尚不清楚，有关TNFAIP8基因功能的报道仍处于起步阶段。本课题拟在前期研究基础上，研究TNFAIP8分子对AML生物学行为的影响；明确TNFAIP8对AML多药耐药的调控作用；阐明TNFAIP8作用结构基础及作用模式；体内探讨靶向TNFAIP8增强AML化疗药物敏感性的可行性。此系统性、原创性研究将提出AML耐药新机制，为难治/复发AML的早期预警和检测提供新的生物标记物，对于提高难治/复发AML诊疗水平具有重要的临床意义。

中文关键词： 急性髓性白血病；多药耐药；TNFAIP8；凋亡

英文摘要： Multidrug resistance (MDR) remains the major cause of relapsed/refractory disease in adults with acute myeloid leukemia (AML) and severely impairs treatment efficiency and survival, thereafter remaining a challenge for AML treatment. TNFAIP8 is a recently discovered antiapoptotic molecule. Accumulating evidence showed that TNFAIP8 was closely related to the regulation of tumor proliferation and invasion. We found that TNFAIP8 was involved in MDR of AML, but the regulatory mechanisms of TNFAIP8 in the MDR of AML remained unclear. Based on our previous results, we exert our joint research on AML patient samples, human multidrug-resistant AML cell lines, Xenotransplantation AML model in NOD/SCID mice and TNFAIP8 knockout mice in vitro and in vivo. Our joint research project will investigate the effect ofTNFAIP8 on the biological behavior of AML; determine the role ofTNFAIP8 in AML chemoresistance; clarify the regulatory patterns of TNFAIP8, and further elucidate the underlying molecular genetic basis of TNFAIP8 in AML chemoresistance. Our original research will provide new mechanisms and putative biomarkers of sensitivity to chemotherapeutics in the relapsed/refractory AML patients, which is of great importance for the enhancement of AMLtreatment efficacy.

英文关键词： acute myeloid leukemia;multidrug resistance;TNFAIP8;apoptosis