2016-08-012024-05-13https://scholars.lib.ntu.edu.tw/handle/123456789/648831摘要：糖尿病視網膜病變(DR)，尤其是增殖性糖尿病視網膜病變(PDR)是造成失明的主要原因之一。雖然近年來有抗血管新生因子療法及微創玻璃體切除手術的發展，但是PDR 的視力預後仍不佳。因此充分了解其致病機轉以及尋找更有效的治療方法以防止PDR 之惡化，是十分迫切的課題。臨床經驗及大型之臨床試驗結果顯示，接受一般血糖控制之糖尿病患，即使在研究結束後，接受更積極之血糖控制，其日後DR 之惡化程度仍高於原先一開始就接受積極血糖治療的病患，這種現象稱為「新陳代謝記憶」。近年來之研究顯示，高血糖引起併發症和「表觀遺傳(epigenetics)」有關。目前已知的表觀遺傳機制包括DNA 甲基化、改變組蛋白(histone)尾端或染色體結構及微型RNA (microRNAs)。近年來臨床上已廣泛採用抗血管內皮細胞生長因子(VEGF)治療DR，但是玻璃體注射anti-VEGF 藥劑後，會產生angio-fibrotic shift 的現象。此現象與結締組織生長因子(CTGF)活化有關。CTGF 可促使結締組織增生，引起牽引性視網膜剝離，導致失明。近來之研究發現，高血糖可以透過表觀遺傳之機制，促進CTGF 之活化及生成，進而影響器官之癒合過程。這些現象在肺、肝、腎及心臟均有大量之研究，但在眼睛特別是視網膜方面則少有報告。因此我們假設外在環境之因素，例如高血糖可以經由表觀遺傳的方法調控 CTGF 在視網膜細胞的表現，進而在PDR 的過程中扮演重要的角色．本計畫是一個為期二年的實驗，第一年我們將進行動物實驗，利用streptozotocin 引發之糖尿病鼠模式研究CTGF 在視網膜之表現，特別是在高血糖之刺激下是否能引起組蛋白中離氨基酸（lysine）在H3K4 及H3K9 位置上之甲基化，進而調控CTGF 的產生，並證實『新陳代謝記憶』之機轉。第二年我們將探討在RF/6A 及ARPE19 細胞中，以高血糖及TGF-β刺激是否能引起microRNA，尤其是miR-133之改變，進而調控CTGF 的合成．希望藉由本次之研究能更明瞭PDR 中CTGF 之調控及其作用機轉，也為PDR 之防治探討一條新的治療方向。<br> Abstract: Proliferative diabetic retinopathy (PDR) represents the most common cause of blindness in peopleof working age. Despite significant advances in the understanding of the pathogenesis of PDR andthe development of new treatment techniques, such as anti-VEGF therapy and microincisionvitrectomy, the prognosis of PDR is still unsatisfactory. Therefore; it is an important issue to searchfor new modalities of prevention and treatment of PDR. Clinical and epidemiologic evidence haveshown that PDR continues beyond the point when good glycemic control has been achieved, andhave suggested a ‘‘metabolic memory’’ phenomenon. Recent data have suggested an importantrole of epigenetic modifications in the metabolic memory phenomenon associated with thecontinued progression of diabetic complications. PDR is characterized by the retinalneovascularization and tractional retinal detachment. Vascular endothelial growth factor (VEGF)and connective tissue growth factor (CTGF) may contribute to the new vessels formation andfibrotic change of PDR respectively. The aim of our study was to investigate the role of epigeneticmechanisms in the regulation of retinal CTGF expression in the development of PDR and also inthe metabolic memory associated with its failure to halt the progression of PDT even afterre-establishment of normal glycemic control.This project will be performed in two years. In the first year, we will evaluate the epigeneticmodification of CTGF expression in retina with a streptozocin-induced diabetic rat model. Wewill investigate the role of epigenetic chromatin marks histone H3K4 and H3K9 lysinemethylation (H3Kme) in retina under high-glucose conditions. In the second year, we willinvestigate the miRNA, especially miR-133, expression patterns involved in CTGF geneexpression using retinal vascular endothelial cells (RF/6A) and ARPE 19 cells under normal andhigh-glucose conditions.Through our intensive study, the epigenetic mechanisms of modulation the expression offibrogenic factor CTGF in the development of PDR will be further understood. The “metabolicmemory” phenomenon in the progression of PDR will be confirmed. Understanding themechanism of CTGF modulation may provide the pharmacologic and other therapies which couldreverse these modifications in the levels of histone methylation or microRNA and have potentialprotective effects for preventing PDR progression.