靶向miR-17~92/NFATC1通路逆转抗CML T细胞免疫缺陷及其分子机制

慢性粒细胞白血病（CML）病人常伴T细胞功能不全，是制约基因修饰T细胞免疫疗效的重要因素，如何逆转该状态研究甚少。我们既往研究发现CML中存在T细胞谱系不全、活化缺陷等，基因表达谱分析推测TCR信号通路中NFATC1（活化的T细胞核因子C1）及其上游miR-17~92可能是关键调控分子。故本研究拟（1）分析miR-17~92/NFATC1在CML病人不同T细胞群和不同免疫状态下T细胞中的变化；（2）通过体外和CML人源化小鼠模型分析靶向调控NFATC1和miR-17~92表达对T细胞功能的影响；（3）分析miR-17~92是否通过调控GSK3β或E2F1-p38MAPK磷酸化，而调控NFATC1活性、抑制IL-2和T细胞活化；最终明确靶向调控miR-17~92/NFATC1能否逆转抗CML T细胞免疫缺陷，深化对CML病人T细胞免疫缺陷的精确分子机制的认识，为其逆转调控提供新靶点和策略。

T-cell immunodeficiency is a common feature in chronic myelogenous leukemia (CML) patients, which is one of the critical reason to limit the effect of gene redirected T cell immunotherapy, little is known how to revise the status. Our previous studies found that the alterations of T cell immunity in CML involved in skewed T cell repertoire, and lower activation etc, based on the gene expression profile analysis, we suppose that nuclear factor of activated T cells C1 (NFATC1) of T cell receptor signal pathway and its upstream regulator miR-17~92 may be the key regulators. Therefore, we aim to investigate (1) the expressed alteration of miR-17~92/NFATC1 in different T cell subsets from CML patients and T cells within different immune status from healthy individuals, (2) the influence on T cell immune function by target regulation of NFATC1 and miR-17~92 in vitro and in vivo by using humanized CML mice model analysis, and (3) to confirm whether miR-17~92 regulate GSK3β or E2F1- p38MAPK phosphorylation, subsequently regulate the activity of NFATC1 and finally inhibit the expression of cytokine such as interleukin-2 (IL-2) and T cell activation in CML. Finally, the role of mediation of miR-17~92/NFATC1 in T cell immunodeficiency will be confirmed and the possibility of inversed regulation and the mechanism will be determined in CML, the precise molecular mechanism of T cell immunodeficiency in different stage will be definite. Overall, the study will provide the novel target and strategy for inversed regulation of T cell immunity in CML patients.