2010-08-012024-05-13https://scholars.lib.ntu.edu.tw/handle/123456789/646802摘要：近五年來，我們針對近視基因體和形成機轉的研究一直投入相當大的心力，我們期望找出近視可能的相關基因和其調控可能因素，進而找出其治療可能的方向。在基因體的研究中我們研究發現高度近視形成過程中lumican的基因啓動子活性表現會影響高度近視是否形成。在動物實驗模式中我們也發現lumican基因在鞏膜中的表現量會影響鞏膜膠原蛋白纖維的排列和粗細，間接影響斑馬魚鞏膜的近視形成過成中變細變薄而造成眼軸過長的現象。在最近的研究中我們更發現性荷爾蒙在血清中的表現量也會影響高度近視的形成速度，例如我們研究顯示HSD17B1的一個基因多型性會影響性荷爾蒙在血清中的濃度，間接影響在男女高度近視形成表現差異。而先前他人的研究也顯示性荷爾蒙在血清中的濃度會影響鞏膜中膠原蛋白纖維受到酵素分解和形成的速度，間接影響眼軸長度和高度近視的形成。因此這一連串的交互影響，造成台灣學童近視表現在男女之間的不同。而性荷爾蒙在血清中的活性不僅受到其合成酵素的調節，也受到其結合攜帶蛋白的調控，例如SHBG和CBG二種血清蛋白也會影響性荷爾蒙對標的組織器官的作用。但是先前的研究中發現不僅基因的多型性會影響外表型的表現，所謂表觀遺傳(epigenetics)也會影響所謂complex disease的形成和表現，雖然先前的基因體研究已有相當的研究成果，我們更進一步的探討表觀遺傳調控(epigenetic regulation)對近視形成的影響，因此本研究計劃的目的是探討1. 研究近視和非近視族群中，總表觀遺傳(epigenomics)的染色體甲基化程度在兩者之間是否有何差別？2. 從總表觀遺傳(epigenomics)的染色體甲基化程度差異間找出可能的近視候選基因？3. 利用現在研究的成果中更進一步探討目前所知的性荷爾蒙基因中其合成酵素或結合攜帶蛋白的甲基化程度。<br> Abstract: Myopia is the most common eye disorder in Taiwan and around the world. Thinning of the sclera is akey feature of human myopia development. The scleral remodeling mechanism, involving theregulation of numerous gene products (mRNAs and proteins) in the extracellular matrix, such ascollagens, proteoglycans, matrix metalloproteinases (MMPs), and tissue inhibitors ofmetalloproteinases (TIMMPs), is an intrinsic precursor to different paradigms of myopia induction.In our previous studies, we found the alteration of a SNP at the lumican, one of small leucine-richproteogrlycans, promoter and its haplotype are strongly associated with the development of highmyopia. Furthermore, we also developed a zebrafish model which showed that knockdown oflumican expression induced a homologue of human myopia and an axial elongation. In our recentstudies, in a case-control study involving a campus-based sample of 290 subjects (142 females and148 males) with high myopia and 286 controls (139 females and 147 males) with low myopia oremmetropia, we found that among the sex steroid synthesis enzyme genes, CYP17, HSD3B1,HSD17B1, SRD5A2, and CYP19A1, myopia risk was observed at the HSD17B1 gene SNPrs605059:G>A, with a significant gender-gene interaction, demonstrated a significant associationwith estradiol levels in males and testosterone levels in females. Estradiol and testosterone levelswere significantly higher, while progesterone and free testosterone levels were significantly lower inthe high myopia group than in controls. In the female subjects, testosterone levels were alsosignificantly higher in these cases than in the controls. In present study, we would like to investigatethe causes of variation of sex steroid hormone in terms of the effect of HSD17B1 (steroid hormonesynthesis enzyme), SHBG and CBG (steroid hormone binding proteins) on the levels and activitiesof sex steroid hormones through a novelly epigenetic approach which might play an important role asthat of genomic approach. Before this candiate gene approach, we will also conduct an epigenomicapproach to investigate the difference of methylation status between myopia and control subjects tofind our possible epigenetic regulation of myopia development. Therefore, the specific aims of ourproposal include:1. Establishment of relationship of HSD17B1, SHBG and CBG methylation statusbetween the high myopia patients and controls.2. Identification of candidate genes and selecting the most relevant candidate3. To determine the methylation status between subjects with high myopia andmatched controls.近視性別myopiagender