SCF激活的c-Kit+细胞经Wnt7通路改善视网膜神经节细胞损伤的作用机制研究

视网膜神经节细胞(RGC)损伤为多种视网膜变性类疾病的共同病理特征，所以通过激活内源性神经保护机制抑制RGC死亡，可有效改善患者视觉功能。申请人长期关注视网膜c-Kit+细胞的功能研究，并在前期动物实验中发现，c-Kit配体SCF可明显改善RGC损伤，且该过程伴随c-Kit+细胞中Wnt7等因子表达上调，提示SCF可能通过激活c-Kit+细胞分泌Wnt7等因子，促进RGC存活。为验证该假说，申请人拟研究：1.小鼠RGC损伤模型中，明确SCF对c-Kit+细胞比例、形态及Wnt7通路等的影响；2.通过阻断Wnt7通路等，研究Wnt7介导SCF/c-Kit对RGC保护的关键作用；3.体外模型中，探索经SCF激活的c-Kit+细胞经Wnt7旁分泌途径促进RGC存活的分子机制。通过上述研究，以期阐述SCF/c-Kit/Wnt7通路对于RGC损伤的保护作用及机制，为视网膜变性类疾病治疗提供潜在靶标。

Retinal ganglion cell (RGC) loss is a hallmark of retinal degeneration (RD) diseases including glaucoma, diabetic retinopathy, etc.. The activation of endogenous neuron-protective mechanism for RGC may serve as a putative therapeutic target for these diseases. The applicant’s research has focused on the protective role of retinal c-Kit+ cells in mammals. She found that c-Kit ligand SCF can alleviate RGC injury, and simultaneously upregulate the expression of factors such as Wnt7 in retinal c-Kit+ cells. Considering that Wnt7 signaling is involved in the protection of various neurons, this result suggests that SCF-stimulated c-Kit+ cell may promote RGC survival via Wnt7 secretion. To verify this hypothesis, the applicant will investigate the following issues in the current project: 1. Demonstrating the effect of SCF treatment on the proportion, morphology and Wnt7 pathway of retinal c-Kit+ cells in the mouse model of RGC injury; 2. Elucidating of the critical role of Wnt7 signaling in SCF/c-Kit-induced RGC protection, by blockade Wnt7 pathways; 3. Deciphering the molecular mechanism of the neuroprotective effect of SCF/c-Kit/Wnt7 pathway in vitro. Taken together, these studies will demonstrate the protective effect and mechanism of SCF/c-Kit/Wnt7 pathway on RGC injury, and provide potential targets for treating retinal degeneration diseases.