芬戈莫德（FTY720）对视网膜光损伤的神经保护机制研究

FTY720(fingolimod), an analogue to the sphingosine, is a unique immune suppressant characterized by sequestration of lymphocytes in secondary lymph nodes and inducing lymphopenia, and inhibition of T lymphocytes infiltration into the central nervous system. Conventionally, it is thought FTY720 is phosphorylated to form FTY720-phosphate (FTY720-P), and then FTY720-P binds to S1P receptors (S1PRs) and thereby shows its immune suppression effect. However, whether FTY720 is limited only as an immune suppressant is of debate. Recently it became evident that the action of FTY720 was more complex as it was found to directly target several other receptors or enzymes. Thus, FTY720 can bind to and inhibit the cannabinoid CB1 receptor, cytosolic phospholipase A2 (cPLA2), S1P lyase and ceramide synthase (CerS) activity. .The light induced retina degeneration (LIRD) model is a non-autoimmune animal model for retina degeneration. The basic pathological change in LIRD is photoreceptor apoptosis. It is clear that ceramide plays a key role in mediating apoptosis, and decreasing intracellular ceramide production can protect photoreceptor against apoptosis in Drosophila and retina degeneration model of RD10..In the LIRD model we found: 1.)the retinal ceramide increased significantly prior to photoreceptor apoptosis；2.)FTY720 could protect the retina against light damage；3.）However, the retinal protection from various dosages of FTY720 was discordant with the decreased extent of peripheral lymphocytes, which indicated the protection of FTY720 to retina might be independent of its immune suppression.So we hypothesized: 1.)in the LIRD model, the conventional immune suppression from FTY720 might not contribute to the retinal protection；2.）FTY720 might inhibit ceramide synthase activity and consequently decrease the ceramide production to protect photoreceptors against apoptosis..In this study, based on our initial results from LIRD model we are planning to detect FTY720's impact on key enzymes' gene/protein expression and activities in ceramide metabolism pathways, and changes of related metabolites to ceramide. Additionally, we'll detect the dosage and temporal effect of FTY720 on peripheral lymphocytes and retinal protection, and measure the local immune suppression effect of FTY720 on the light stressed retina..The study on retinal protective mechanism of FTY720, independent of immune suppression, might show its potent neuroprotective application to non-immune diseases, and be also valuable to develope the medicine for the prevention and treatment of the light-induced retinal damage.

FTY720是鞘氨醇结构类似物，具有独特的免疫抑制作用，但其作用是否仅仅局限于免疫抑制目前存在争论。新的研究发现FTY720能抑制神经酰胺合成酶进而减少神经酰胺的产生。视网膜光损伤的基本病理改变是感光细胞凋亡。研究表明减少神经酰胺能阻止感光细胞凋亡。.我们初步研究发现：1）在光损伤中，视网膜神经酰胺显著升高；2）FTY720能保护视网膜光损伤；3）该保护不依赖于对外周血淋巴细胞的抑制。故我们推测：在光损伤中，FTY720的免疫抑制可能没有参与对视网膜的保护；FTY720可能通过抑制神经酰胺合成酶，减少神经酰胺而阻滞感光细胞凋亡。.我们拟在现有基础上研究：1）FTY720对视网膜神经酰胺代谢及关键酶（基因/蛋白表达,酶活性）的影响；2）从不同角度研究免疫抑制是否参与对视网膜的保护。.本研究对于拓展FTY720作用机制的认识，研发视网膜光损伤的药物具有重要意义。

芬戈莫德（FTY720）是鞘氨醇结构类似物，具有独特的免疫抑制作用，但其作用是否仅仅局限于免疫抑制存在争论。.我们以大鼠视网膜光损伤为模型，研究FTY720对视网膜光损伤的保护作用及机制。.通过该项目的实施，我们建立了稳定的大鼠视网膜光损伤模型，该模型的建立为研究视网膜光损伤奠定了模型基础。我们发现了FTY720对大鼠视网膜光损伤的保护效应，表现为在组织结构和功能上的保护，该发现为开发FTY720在视网膜光损伤的应用奠定了基础。我们发现在大鼠视网膜光损伤过程中，神经酰胺的从头合成介导了视网膜感光细胞的凋亡，该结果揭示了视网膜凋亡新的分子机制，为从神经酰胺的角度发现视网膜光损伤保护药物奠定了实验基础。我们发现FTY720通过抑制神经酰胺的从头合成对大鼠视网膜产生保护效应，该发现为开发FTY720在视网膜光损伤的应用奠定了药理学基础。