Flt3L在糖尿病微血管病变早期诊断中的价值及其致病机制研究

微血管病变是糖尿病患者常见且严重的慢性并发症，严重影响患者的生活质量，但目前仍缺乏糖尿病微血管病变的早期诊断标志物，且对其发病机制尚未完全明确。基于组织缺氧和微血管内皮细胞损伤是糖尿病微血管病变发生的关键，我们前期以此为切入点，研究发现，缺氧可激活微血管内皮细胞（HRMEC）膜上细胞增殖发育相关分子Flt3，继发PI3K/AKT/mTOR及ERK/p90RSK/S6通路的改变，从而影响细胞的生物学功能；同时，Flt3配体（Flt3L）在早期糖尿病微血管病变患者血清中显著升高。因此，本项目拟进一步扩大样本量评估Flt3L对糖尿病微血管病变的诊断价值；利用HRMEC缺氧模型探究Flt3在HRMEC损伤中的分子机制；并利用体内db/db小鼠糖尿病模型评价靶向Flt3治疗糖尿病微血管病变的可行性。本项目将从全新的视角阐明糖尿病微血管病变的发病机制，为发展新的早期精准诊断和治疗靶点奠定基础。

Microangiopathy is a common and serious chronic complication in patients with diabetes mellitus, and will worsen the quality of life. However, there are still no ideal biomarkers for early diagnosis of diabetic microangiopathy, and its pathogenesis hasn’t been fully understood. Hypoxia and microvascular endothelial cell damage have been known to be the key of the occurrence of diabetic microangiopathy, our previous study had also found that hypoxia could activate proliferation and development related molecule Flt3 located on the membrane of human retinal microvascular endothelial cells (HRMEC), and induce the change of PI3K/AKT/mTOR and ERK/p90RSK/S6 signaling pathways, thus affecting the cellular biological function. Meanwhile, serum Flt3 ligand (Flt3L) levels in the patients with early stage of diabetic microangiopathy increased significantly. In the current study, we aim to further evaluate the diagnostic value of Flt3L for diabetic microangiopathy; then, the hypoxic model of HRMEC is used to explore the molecular mechanisms by which Flt3 inducing the damage to HRMEC; finally, in vivo db/db diabetic model is used to evaluate the feasibility of targeting Flt3 to treat diabetic microangiopathy. This project will shed light on the pathogenesis of diabetic microangiopathy from a new perspective, and lay foundation for developing new early diagnostic and therapeutic targets.