2011-08-012024-05-14https://scholars.lib.ntu.edu.tw/handle/123456789/655999摘要：糖尿病視網膜病變是導致視力喪失的重要疾病之一。尋找適當的藥物以抑制糖尿病視網膜病變的惡化是一個重要的課題。新的證據指出慢性發炎反應及氧化壓力所產生過量的活性氧(reactive oxygen species，ROS)，是導致糖尿病視網膜病變的關鍵所在。Nuclear factor-κ B (NF-κB) 是特定基因重要的調節因子，參與了發炎和免疫反應、增殖及細胞凋亡。氧化壓力可以藉由ROS 活化NF-κB，然後控制免疫媒介物的表現。在視網膜中，因高血糖而活化的NF-κB 會誘發微血管內皮細胞的細胞凋亡及視網膜的發炎反應，所以利用藥物以抑制NF-κB的活化將有效防止糖尿病視網膜病變的進展。另外，近年來在代謝症候群及糖尿病方面的研究發現脂肪細激素adiponectin和糖尿病的產生相關，但是與糖尿病視網膜病變之關係尚無定論，值得作進一步的研究。PPARs 是一群細胞核內接受器(nuclear receptors)，可分為三種次型家族，分別為PPAR-α、PPAR-γ 與 PPAR-β/δ。研究顯示PPAR 會影響轉錄因子的活動，例如AP-1、NF-κB、STAT-1，進而影響cytokines 的合成。近年來有2 篇臨床試驗報告Effect offenofibrate on the need for laser treatment for diabetic retinopathy (FIELD study) 及Actionto Control Cardiovascular Risk in Diabetes (ACCORD) Eye Study 發現 fenofibrate 這種peroxisome proliferator-activated receptor-alpha (PPAR-α) agonist 可以降低糖尿病人接受全網膜雷射治療的機會，而機轉仍不清楚。由於有其他研究發現fenofibrate 可以在糖尿病大鼠的腎臟組織抑制與nuclear factor-κ B (NF-κB)相關的發炎反應。因此，本研究的中假說認為：「糖尿病因NF-κB 所調控的發炎反應的上升，相關的chemokines 包括MCP-1、ICAM-1、及FKN 都會增加，使得視網膜上產生局部白血球聚集及浸潤，誘發發炎現象及組織缺氧，並使內皮細胞產生移行、導致血管新生，進而使糖尿病視網膜病變惡化。使用Fenofibrate 來治療糖尿病抑制NF-κB 的活化，連帶抑制它所調控的MCP-1、ICAM-1、及FKN 的產生，達到抑制視網膜的局部發炎反應，延緩糖尿病視網膜病變的效果。」本計畫是一個為期三年的研究。第一年，我們將以糖尿病大鼠模式，使用fenofibrate 治療，研究其對於糖尿病視網膜病變相關的、受NF-κB 調控的發炎介質有何影響，我們將利用反轉錄-聚合酶連鎖反應、西方墨點法、酵素連結免疫吸附分析及免疫組織染色法等方式，研究其玻璃體及視網膜上NF-κB P65、intercelullar adhesionmolecule (ICAM)-1、MCP-1 及fractalkine (FKN)等chemokines 的表現。第二年，我們將以培養之視網膜血管內皮細胞為對象，測定細胞在高葡萄糖濃度下是否表現MCP-1，以fenofibrate處理是否抑制表現MCP-1之表現，同時研究其相關之訊息傳遞機轉。第三年，我們將以糖尿病大鼠模式，使用fenofibrate 治療，研究玻璃體及視網膜上脂肪細激素adiponectin之表現，同時以培養之視網膜血管內皮細胞為對象，測定細胞在高葡萄糖濃度下以fenofibrate處理是否影響adiponectin之表現，同時研究其相關之訊息傳遞機轉。由於在已開發中國家的工作人口中，糖尿病視網膜病變仍然是造成失明及視力不良的首要原因。希望基於我們實驗結果能找出治療糖尿病視網膜病變的新方法或是新藥物及其作用機轉，以減少因糖尿病視網膜病變引起視力喪失的機會。<br> Abstract: Diabetic retinopathy represents the most common cause of blindness in people ofworking age. Despite significant advances in the understanding of the pathogenesis of DR, themajor treatments for DR, including retinal photocoagulation and vitrectomy, have mostlyremained the same for many years. Therefore; it is an important issue for health careproviders to search for new modalities of prevention and treatment of DR.Fenofibrate, a member of peroxisome proliferator-activated receptor (PPAR)-αagonists, is used to lower levels of cholesterol and other lipids in the blood. In FenofibrateIntervention and Event Lowering in Diabetes (FIELD) study and Action to ControlCardiovascular Risk in Diabetes (ACCORD) Eye Study, the requirement for laser treatmentfor all retinopathy was significantly lower in patients taking fenofibrate than in the placebogroup. These studies suggest that fenofibrate might prevent the need for laser treatment indiabetic retinopathy by inhibiting apoptosis of retinal endothelial cells, preventing cellularmigration, and reducing local inflammatory processes, with implications for pathologicalprocesses such as retinal capillary leakage. However, the actual mechanisms by whichfenofibrate might improve microvascular outcomes are needed to be clarified. PPARαagonists are reported to inhibit angiogenesis, inflammation, and cell migration. Fenofibratehas been proved to regulate retinal endothelial cell survival and to prevent apoptotic celldeath.In the present study, we hypothesize that fenofibrate can inhibit the activation ofNF-κB and its downstream inflammatory mediators in diabetic retinas, and also can reduceoxidative stress within diabetic eyes, therefore prevent diabetic retinas from DR progression,as the clinical findings observed in the FIELD and ACCORD Eye Study. In the first year,we will use a streptozotocin(STZ)-induced diabetic rat model to verify the role of NF-κBactivation in DR. The retina tissue of these rats will be investigated to clarify the effects offenofibrate on ocular oxidative damage and inflammatory chemokines regulated by NF-κB.Since fenofibrate inhibits the vascular inflammatory response by interfering with the NF-κBtransactivation. Thus, in the second year, we will investigate the effect of fenofibrate on theexpression of MCP-1 in retinal vascular endothelial cells exposed to high glucoseconcentration and the mechanisms involved. Since fenofibrate therapy reducespro-inflammatory biomarkers and improves adiponectin levels in diabetic patients.Therefore, in the third year, the mechanisms and effect of fenofibrate on the expression ofadiponectin and its receptors will be examined in cell culture model and diabetic rats model.DR is still the leading cause of blindness in our society; search for new treatment modalitiesto prevent the progression of DR is an important issue. Through our study, the biochemical orpathophysiological evidence about the relationship between fenofibrate therapy andprogression of DR will be clarified and provide a new therapeutic avenue of DR.糖尿病視網膜病變PPAR-αFenofibrate脂締素(Adiponectin)