| 摘要: | 隨著地球大氣層遭到破壞，愈來愈多紫外光穿透大氣層，尤其是UVB (Ultra Violet B, 280 nm-320 nm)因具有高階能量可導致皮膚細胞之DNA受損及誘導發炎現象，甚至於引發非黑色素瘤皮膚癌，因此近年來引起研究學者的高度關注。過去，UVB誘發的相關現象已利用不同的細胞組織或人工皮膚培養方法被研究過，然而使用不同的組織模式來研究UVB的影響，所得的結果常不相互吻合。為了有系統地瞭解UVB所誘發的訊息路徑，在計畫的第一部份我們將建立以UVB誘導的斑馬魚皮膚損傷模式，藉由優化UVB強度、暴露的時間長短來尋找出一個有別於過去僅用部分表皮組織的動物模式。接著，在第二部分，利用已經建立的斑馬魚模式，利用現今基因微陣列與生物訊息分析的優點，我們將進行斑馬魚全組織基因表現圖譜分析(whole organism gene profiling)來確認UVB所誘發的早期生物標記，並在第三與第四建立轉基因斑馬魚的活體篩檢平台，進而利用這些標記來篩檢能修復UVB損傷的物質。根據過去與中國杭州生技公司共同開發膠原蛋白在修復皮膚損傷的經驗，我們也將針對UVB誘發的損傷來測試膠原蛋白最佳的作用條件與分子機制的分析。同時，也將此技術應用於激脢抑制物的篩選。倘若計畫順利進行，我們將有機會全盤了解UVB誘發皮膚損傷的機制與相關基因網絡，並且活用此篩選平台，找出最有潛力的修復物質應用於臨床。
Ultraviolet radiation, categorized by wavelength into UVC (200–280 nm), UVB (280–320 nm) and UVA (320–400 nm), has the ability to ionize molecules and induces a series of chemical reactions. Compared with the UV dosage we exposed in the past, more UVB and UVC radiation reach to earth ground due to decrease of ozone layer. Over exposure to solar UVs causes acute and chronic health issues that may be irreversible. In addition, UV induces synthesis of Matrix Metalloproteinase (MMPs), which decomposes collagen fibrils and inhibits procollagen synthesis, leading to disorganized dermal skin tissue structure. Moreover, cells produce Reactive Oxygen Species (ROS) after prolonged exposure, which causes DNA damages, unbalances immune system, and finally leads to skin cancer.Taken advantage on accessibility of serial gene profiling and high throughput data, UVB-associated phenomenon in human cultured cells or full rack of human skin were investigated. However, discrepant results occurred with different tissue models may lead ambiguity in UVB-induced pathway. In order to understand UVB-associated reactions systematically, we have established zebrafish model in Aim 1. Serial biological examination, such as optimization of UVB dosage, time-course experiment will be conducted. Moreover, p53-associated markers, inflammatory response will be performed. Next, in order to systematically analyze the UVB-induced network, whole organism gene profiling to identify a novel biomarker in Aim 2. Our findings will establish a permissive model that applies to serve as a platform for further screening on UV-related treatment in Aim 3 and 4. According to our previous work on analyzing effects of collagen extract, we will optimize the ratio of collagen extracts on UVB-induced wound healing, and in Aim 3. In addition, kinase inhibitors will be screened as potential therapeutic candidate in Aim 4. As our proposal accomplished, a solid, comprehensive understanding on UVB-induced pathway will be elucidated, and the drug screening will consider as a clinical strategy on UVB damage. |
