细胞膜磷脂酰肌醇重构与T细胞恶性转化的机制研究

细胞膜（PM）磷脂酰肌醇（PIPs）重构是肿瘤细胞的显著特征，但PIPs重构机制及其是否在体导致肿瘤发生依然未知。我们发现，ORP4L在T细胞不表达但T白血病细胞高表达，ORP4L基因敲入小鼠自发发展为T细胞白血病；同时，这类T细胞PM PIPs被重构。利用该小鼠模型，结合PIPs荧光探针定位和脂质组学分析等，我们将证明：ORP4L和同家族蛋白OSPB相互作用、控制OSBP携带PI（4）P从高尔基体移动到PM以供PI(4,5)P2合成；从而导致PM PIPs重构，并依次启动了PI3K/AKT过激活、组蛋白异常乙酰化、表观遗传修饰和T细胞恶性转化；我们也在体评估ORP4L抑制剂对T细胞白血病治疗的效果。因此，本项目将揭示这个新的脂质转运系统导致PM PIPs重构，作为起始因素，引发了T细胞恶性转化；结果有望提供T细胞白血病发生机制的创新解释，并奠定转化该科学发现到临床实践的基础。

Plasma membrane (PM) phosphoinositides remodeling represents a cancer-associated change of cells. However, it is unclear how the PM phosphoinositides is regulated and whether their changes result in tumorigenesis in vivo. ORP4L, a multiple lipids binding protein, is expressed in T-leukemia cells but not normal T-cells, and an astonishing finding that 100% ORP4L knock-in (KI) mice develop T-cell leukemia. PM phosphoinositides in T cell of ORP4L KI mice has been remolded. In this study, by hiring ORP4L KI mice model, PIPs fluorescent biosensors probe and other methods, we will identify that ORP4L may drive OSBP translocation cargoing PI(4)P from the Golgi complex to the PM for PI(4,5)P2 biosynthesis, ORP4L thereby establishes an unexpected non-vesicular lipid transport model, resulting in PM phosphoinositides remodeling, PI3K/AKT hyperactivation, excessive histone acetylation and epigenetic modification. Moreover, we will test if the inhibition of ORP4L by small molecules will destroy efficiently T leukemia cells in vivo. The present results will provide a plausible mechanism for T-cell malignant transformation and leukemogenesis and ORP4L inhibition represent a potential target for T-cell leukemia prevention and treatment.