GLUT1相关信号通路在婴儿血管瘤增生及消退机制中的研究

Infantile hemangioma is a blood vessel proliferative disease with high incidence, long duration. It has serious influence on children's physical and mental health. The key for the treatment of infantile hemangioma is to limit tumor growth in the proliferating period, and enhance apoptosis and cell differentiation in the involuting period. Our previous study found that the expression of GLUT1 in hemangioma decreased during the transition from proliferating to involuting, in which IGFⅡ/IGF2R and AKT/PI3K pathway were both activated in the proliferating period of hemangioma, and they were involved in proliferation and apoptosis of hemangioma. In addition, our study using GFP labled GLUT1 positive hemangioma stem cells demonstrated that it was the main source of adipocyte in the involuting period of hemangioma. GLUT1 is involved in the regulation of proliferation and apoptosis in various types of tumors. however, its role in the regulatory pathway of hemangioma has not been reported. Based on our findings, we hypothesized that GLUT1 could regulate the proliferation, apoptosis and differentiation in infantile hemangioma. Our research project aims to verify the regulatory mechanism of GLUT1 through HIF-1α/P53,IGF2/AKT/PI3K and HIF-1α/AKT pathway in proliferation, apoptosis and differentiation of infantile hemangioma using cellular, animal model and clinical samples which will facilitate to address the regulatory mechanism involved in the formation of infantile hemangioma and novel therapeutic measures.

婴儿血管瘤发病率高，病程长，严重影响儿童生理和心理健康。治疗婴儿血管瘤的关键在于发病增生期控制瘤体生长速度，在消退期加速其凋亡及细胞分化。课题组前期研究发现，GLUT1在血管瘤中表达量从增生期到消退期逐渐下调，IGFⅡ/IGF2R及AKT/PI3K通路在增生期血管瘤中异常活化，且IGFⅡ/IGF2R和 AKT/PI3K通路均参与血管瘤的增殖、凋亡的调控。同时，我们通过GFP标记GLUT1阳性的血管瘤干细胞，发现其是消退期脂肪细胞的主要来源。GLUT1在多种癌症中参与调控增殖、凋亡，而其在血管瘤中的作用机制尚未报道。因此，我们推断GLUT1参与调控婴儿血管瘤增殖、凋亡及分化。本研究拟从临床标本、细胞、分子以及动物实验水平来验证，GLUT1通过HIF-1α/P53、IGF2/AKT/PI3K及HIF-1α/AKT通路调控婴儿血管瘤增殖凋亡及分化，以期为婴儿血管瘤临床治疗找到新的突破口。

婴儿血管瘤发病率高，病程长，严重影响儿童生理和心理健康。婴儿血管瘤目前总体治疗效果不理想，副作用普遍存在，各种并发症时有发生。出现这一系列问题的关键在于IH的具体发病机制仍不明确。治疗婴儿血管瘤的关键在于发病增殖期控制瘤体生长速度，在消退期加速其凋亡及细胞分化。体外研究表明，血管瘤干细胞是血管瘤增殖期快速生长的关键原因。血管瘤干细胞阳性表达GLUT1，血管瘤内皮细胞GLUT1阳性表达率从增殖期到消退期逐渐降低。GLUT1在婴儿血管瘤细胞中调控细胞增殖、凋亡及分化的作用机制尚不清楚。同时，我们通过GFP标记GLUT1阳性的血管瘤干细胞，发现其是消退期脂肪细胞的主要来源。GLUT1在多种癌症中参与调控增殖、凋亡，因此我们推断GLUT1参与调控婴儿血管瘤增殖、凋亡及分化，以期为婴儿血管瘤临床疗找到新的突破口。.本课题主要研究缺氧对GLUT1在血管瘤中表达的影响，GLUT1在婴儿血管瘤增殖期及消退期中的作用，婴儿血管瘤中GLUT1参与的增殖与凋亡作用机制的研究，GLUT1在血管瘤消退后期血管瘤干细胞的成脂分化研究，血管瘤动物模型的建立及动物实验研究。.缺氧条件下，GLUT1在血管瘤组织中表达上调；血管瘤组织增殖期GLUT1表达明显高于消退期；GLUT1在增殖期血管瘤中的阳性表达率高达83.8%，在消退期的阳性表达率仅为28%，高于其他分子的阳性表达率；在消退期，GLUT1表达下调，血管瘤组织开始坏死凋亡；增殖期HAs中ROCK、Ki-67、PCNA、VEGF/VEGFR2、HMGB1等表达均上调，而P53和Caspases 3表达下调。血管瘤增殖期，HIF1α的表达较高， HIF1α过表达质粒转染后，血管瘤内皮细胞活性增强；HIF1α敲减后，血管瘤内皮细胞活性降低；成功构建了血管瘤裸鼠模型。.血管瘤发病机制复杂，研究其发病机制是一项充满挑战但有着重要意义的工作。血管瘤形成机制的探索研究对于制定血管瘤治疗策略具有重要的指导意义，为开发潜在的抗血管瘤药物奠定理论基础。