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研究生:游建章
研究生(外文):Jian-Jang You
論文名稱:血管增生因子在增殖性糖尿病視網膜病變角色之探討
論文名稱(外文):Clinical and Basic Research of the Angiogenic Factors in Proliferative Diabetic Retinopathy
指導教授:陳慕師陳慕師引用關係郭明良郭明良引用關係楊長豪楊長豪引用關係
指導教授(外文):Muh-Shy ChenMin-Kiang KuoChang-Hao Yang
口試委員:楊偉勛楊中美陳建同翁林仲
口試日期:2010-10-22
學位類別:博士
校院名稱:國立臺灣大學
系所名稱:臨床醫學研究所
學門:醫藥衛生學門
學類:醫學學類
論文種類:學術論文
論文出版年:2010
畢業學年度:99
語文別:中文
論文頁數:188
中文關鍵詞:血管新生增殖性糖尿病視網膜病變血管增生因子血管內皮細胞訊息傳遞
外文關鍵詞:Angiogenesisproliferative diabetic retinopathyangiogenic factorendothelial cellsignal transduction
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糖尿病是開發中及已開發中國家主要視力失明的主要原因之一。糖尿病視網膜病變病人比非糖尿病病患失明率高逹二十五倍。良好的血糖控制可以延緩糖尿病視網膜病變的發生及惡化,並減少視力的喪失。最近三十多年來,糖尿病視網膜病變的治療已從視網膜雷射光凝固治療,進展到早期接受玻璃體視網膜手術及藥物治療。增殖性糖尿病視網膜病變(proliferative diabetic retinopathy, PDR)的治療以雷射視網膜光凝固治療為主,除此,雷射視網膜光凝固治療的適應症是臨床明顯性黃斑水腫(clinically significant macular edema, CSME)及高危險性增殖性糖尿病網膜病變。嚴重的增殖性糖尿病視網膜病變病人合併有併發症者,須接受坦部玻璃體手術。嚴格的血糖控制可以降低視網膜病變的發生率,但是如果能在增殖性糖尿病視網膜病變產生之前或增殖性糖尿病視網膜病變產生時就針對其作治本式治療,將會是我們所希望逹到的。最近針對VEGF (Vascular endothelial growth factor),發展以玻璃體內注射抗VEGF的藥物對於廣泛視網膜水腫及增生的血管退縮可以得到很好的效果。
即使抗VEGF的藥物可抑制大部份的視網膜血管增生,但是第一、它不能完全抑制視網膜的血管新生,及其作用時間有一定的期限。而且抗VEGF的藥物也被發現有其不良反應被報告。例如:發生視網膜色素層撕裂(reinal pigment epithelium tear, RPE tear)的併發症,及拉扯性視網膜剝離的危險增加。第二、抗VEGF並無法抑制血管新生後的纖維化作用。第三、我們希望在未形成視網膜血管增生之前,研究新生因子試圖去抑制糖尿病視網膜病變的發生。因此,我們的研究就在於找尋其他和增殖性糖尿病視網膜病變形成有關的血管新生因子,並了解它們的作用機轉,以期將來成為治療增殖性糖尿病視網膜病變的新標的。本論文的宗旨為血管新生因子在增殖性糖尿病視網膜病變之臨床與基礎相關研究。論文分為五大部份。
因此本論文第一部分,針對血管新生因子fractalkine作研究。在眼球發炎及血管增生病理發生上,扮演了何種重要的角色。Fractalkine曾被發現可表現於不同的眼球組織上,而許多發炎性因子可調節fractalkine的表現。最近,在類風濕性關節炎病人的關節液研究中發現,fractalkine可誘發內皮細胞移行作用及管狀物形成,因而可視為一種血管增生因子。本研究的目的在研究fractalkine誘發血管新生作用,及進一步了解fractalkine在眼睛血管增生性疾病,如增殖性糖尿病視網膜病變參與了什麼重要的步驟。
本實驗培養人類臍靜脈內皮細胞及牛視網膜微血管內皮細胞,利用此兩種內皮細胞研究fractalkine的內皮細胞移行作用及管狀物形成作用。藉著兔子角膜血管新生模式,研究fractalkine的血管新生作用。使用氧氣誘發視網膜病變小鼠(oxygen-induced retinopathy of mice, OIR)模式,試圖以眼球玻璃體內注射抗fractalkine抗體去抑制視網膜血管新生。利用反轉錄酶-聚合酶鏈反應放大研究(RT-PCR)及西方墨點方法分析內皮細胞上fractalkine及其受體CX3CR1的表現。同時收集增殖性糖尿病網膜症病人的玻璃體,利用酵素結合免疫吸收分析方法,定量fractalkine的濃度,並和VEGF作比較。同時利用fractalkine抗體進行免疫消耗作用,以增殖性糖尿病網膜症病人的玻璃體進行內皮細胞移行作用,以了解fractalkine在此類疾病中的角色。結果發現,Fractalkine可明顯引發此兩種內皮細胞的移行作用,同時也可比對照組可促使較多的內皮細胞管狀物形成。在角膜血管新生作用分析中,fractalkine可在兔子的角膜上引起明顯的新生血管。在氧氣誘發視網膜病變小鼠模式,眼球玻璃體內注射抗fractalkine抗體可明顯抑制視網膜血管新生。同時,此兩種內皮細胞都可表現fractalkine及其受體CX3CR1。在分析收集的病人玻璃體進行分析發現,在增殖性糖尿病視網膜病變病人玻璃體中fractaline濃度明顯增加。在利用抗fractalkine抗體進行增殖性糖尿病視網膜病變病人玻璃體免疫消耗後,誘發內皮細胞移行作用也有36.6%的抑制。因此,本實驗結果顯示fractalkine為一個重要血管新生因子,且在眼睛血管新生性疾病致病機轉中,如增殖性糖尿病網膜病變,為重要的參與因子之一。這也提供我們在研究治療這此類疾病時,一個新的標的。
本論文第二部份,根據第一部份的模式,研究Cyr61(cysteine-rich 61)在增殖性糖尿病網膜病變致病機轉上的角色。本實驗主要目的以視網膜內皮細胞模式中及動物模式,研究Cyr61在增殖性糖尿病視網膜病變的致病機轉上有何重要角色。本實驗培養猴子脈絡膜視網膜內皮細胞(RF/6A),利用此內皮細胞研究內皮細胞增殖作用、移行作用、及管狀物形成作用。利用反轉錄酶-聚合酶鏈反應放大研究(RT-PCR)及西方墨點方法分析內皮細胞在缺氧環境下Cyr61的mRNA及蛋白質的表現。藉著氧氣誘發視網膜病變小鼠模式,研究Cyr61在視網膜血管新生的表現。並且,利用抗Cyr61抗體進行氧氣誘發視網膜病變小鼠模式中的小鼠玻璃體注射,試圖去抑制氧氣誘發視網膜病變小鼠的視網膜血管增生。並以streptozocin (鏈脲菌素)去引發糖尿病大鼠模式,以了解在高血糖的大鼠視網膜上Cyr61的表現。同時收集增殖性糖尿病網膜病變病人的玻璃體,利用酵素結合免疫吸收分析方法,定量Cyr61的濃度,並和VEGF作比較。同時利用Cyr61抗體進行免疫消耗作用,以增殖性糖尿病視網膜病變病人的玻璃體進行內皮細胞移行作用,以了解Cyr61在此實驗中的角色。結果發現,Cyr61蛋白中可明顯促進視網膜血管內皮細胞的增殖作用,移行作用,及內皮細胞管狀物形成。在細胞缺氧實驗中,Cyr61的mRNA及蛋白表現明顯增加。在氧氣誘發視網膜病變小鼠模式模式中,Cyr61明顯的表現在增生的視網膜新生血管上。以抗老鼠Cyr61抗體注射於右眼,明顯比注射非特異性免疫球蛋白G左眼,視網膜血管新生受到抑制。在streptozocin引發糖尿病大鼠的視網膜上也有明顯的Cyr61的表現。收集的玻璃體液中Cyr61濃度和VEGF一樣,增殖性糖尿病視網膜病變病患明顯比對照組高,特別是活動型增殖性糖尿病視網膜病變病患。活動型增殖性糖尿病視網膜病變的玻璃體以抗Cyr61抗體進行免疫消耗後,其引發的內皮細胞移行作用明顯受到抑制。因此,Cyr61為一個重要血管新生因子,且在眼睛血管新生性疾病致病機轉中,如增殖性糖尿病視網膜病變佔有重要的地位。因此此因子將可成為我們在研究治療這此類疾病時一個重要的標的。
第三部份,承第二部份,本實驗主要目的在研究增殖性糖尿病視網膜病變病患,術前使用抗VEGF抗體治療增殖性糖尿病視網膜病變對玻璃體液中Cyr61濃度的影響及Cyr61因子角色的再探討。本實驗收集七十五位增殖性糖尿病視網膜病變病人、十五位非增殖性糖尿病視網膜病變之糖尿病黃斑水腫病患及二十五位非糖尿病病患在手術中取得的玻璃體液,在七十五位增殖性糖尿病視網膜病變病人中,五十六位為活動型增殖性糖尿病視網膜病變病患,十九位為非活動型增殖性糖尿病視網膜病變病患。另外收集十六位活動型增殖性糖尿病視網膜病變病患,病患於手術前一週先接受玻璃體內抗VEGF藥物(1.25mg Avastin)注射治療,收集的玻璃體利用酵素結合免疫吸收分析方法定量Cyr61濃度,同時也測定VEGF濃度作比較。利用邏輯斯迴歸分析,研究Cyr61,VEGF是否為可預測的危險因子。同時觀察利用抗VEGF藥物抑制VEGF後,對Cyr61表現的影響。分別收集術前有或無使用抗VEGF抗體治療的活動型增殖性糖尿病視網膜病變病人在手術中移除的增生視網膜前纖維膜,進行組織免疫染色,以了解Cyr61在此纖維化組織中的表現。同時,進一步,利用Cyr61刺激視網膜色素上皮細胞引發膠原蛋白收縮實驗,去研究Cyr61是否也有促進纖維化的作用,以研究在增殖性糖尿病視網膜病變中視網膜纖維膜形成的機轉。結果顯示,在增殖性糖尿病視網膜病變病人及非增殖性糖尿病視網膜病變黃斑水腫糖尿病患的玻璃體中Cyr61蛋白濃度明顯增加,特別是活動型增殖性糖尿病視網膜病變組病人。邏輯斯迴歸分析顯示,玻璃體液中Cyr61和VEGF濃度為一獨立可預測增殖性糖尿病視網膜病變分期的重要因子。術前一週先接受玻璃體內抗VEGF藥物(1.25mg Avastin)治療,稍微下降Cyr61在玻璃體中的濃度,但不能有效抑制Cyr61的表現。另外,在活動型增殖性糖尿病視網膜病變病人的增生視網膜纖維膜上,Cyr61明顯的表現在血管內皮細胞及纖維母細胞上。利用Cyr61刺激視網膜色素上皮細胞引發膠原蛋白收縮實驗,發現Cyr61除了在增殖性糖尿病視網膜病變致病機轉上,除了有血管新生作用外,也有促進纖維化的作用。如此,此證實Cyr61在增殖性糖尿病視網膜病變致病機轉上有其相當的重要性,使Cyr61將來成為治療此類疾病的重要性更為增加。
第四部份研究,承以上第二及第三部份的結果,了解了Cyr61在增殖性糖尿病視網膜病變的致病機轉上參與了重要的角色。進一步,我們想了解視網膜血管內皮細胞在缺氧環境下引發Cyr61表現之機轉。缺氧是糖尿病視網膜病變致病機轉中最重要的因子之一,Cyr61為一個血管增生因子。本實驗的主要目的在研究視網膜血管內皮細胞在缺氧的環境下誘發Cyr61的表現,同時研究其誘發轉錄調控的訊息傳導。研究發現,視網膜血管內皮細胞在缺氧下可引發Cyr61的mRNA及蛋白的表現。同時發現此細胞在缺氧下除了活化HIF-1α外,也促進c-Jun的磷酸化。缺氧會使c-Jun磷酸化,而且利用JNK抑制劑不但抑制c-Jun磷酸化,也抑制了Cyr61的表現。而且在Cyr61的啟動子(promoter)序列上有AP-1及HIF-1-like的結合位置(hypoxia-response element, HRE),利用帶有Cyr61啟動子序列及發luciferase冷光的殖體轉殖入細胞研究、EMSA (electrophoretic mobility shift assay)、免疫沈澱、染色質免疫沉澱分析發現,視網膜內皮細胞在缺氧下可經由活化c-Jun/AP-1及HIF-1α,共同作用在Cyr61啟動子序列的AP-1結合位置上,藉以調控Cyr61的基因轉錄。這使我們對Cyr61在PDR的致病機轉作用上的了解更進一步。
第五部份,在眼球的血管新生上的作用上,integrins伴演了重要的角色。來自蛇毒血清的disintegrins含有RGD胜肽,含有RGD胜肽的disintegrins,可作用在和一些和血管增生有關的integrins上,可抑制血管新生作用。本實驗主要目的在研究蛇毒血清蛋白中disintegrins (解聯蛋白)對視網膜血管新生的抑制作用。本實驗培養牛視網膜微血管內皮細胞,藉著此細胞膜式、氧氣誘發小鼠視網膜病變模式及化學傷害誘發大鼠角膜血管新生模式,研究disintegrins對血管新生的抑制作用。同時收集增殖性糖尿病網膜病變病人的玻璃體,利用蛇毒血清蛋白中的disintegrins去抑制增殖性糖尿病網膜病奱病人的玻璃體所誘發的內皮細胞移行作用,以了解蛇毒血清蛋白中的disintegrins在此類疾病中的角色。利用西方墨點方法分析蛇毒血清蛋白中的disintegrins對內皮細胞在fibronectin刺激下活化Focal adhesion kinsase (FAK)的抑制作用。進行流式細胞分析及細胞免疫螢光染色,研究disintegrins是否經由引發細胞凋亡來抑制血管新生。結果發現,蛇毒血清蛋白中的disintegrins可明顯抑制bFGF所引發的內皮細胞的移行反應,內皮細胞管狀物形成,及細胞黏合作用。在氧氣誘發小鼠視網膜病變模式中,玻璃體內注射微量的蛇毒血清蛋白中的disintegrins可明顯抑制視網膜的血管新生。以disintegrins治療化學傷害引發的大鼠角膜時,可明顯抑制角膜的血管新生。在利用蛇毒血清蛋白中的disintegrins作用增殖性糖尿病網膜病變病人玻璃體後,誘發內皮細胞移行作用也有明顯的抑制。同時,進一步發現,蛇毒血清蛋白中的disintegrins可明顯抑制fibronectin刺激下,下游FAK (focal adhesion kinase)的磷酸化。流式細胞分析及細胞免疫螢光染色結果顯示,disintegrins可誘發血管內皮細胞凋亡。因而disintegrins可能經由引起內皮細胞凋亡,進而抑制血管新生。本實驗結果顯示蛇毒血清蛋白中的disintegrins有明顯的抑制視網膜血管新生的作用,特別是動物模式中可明顯抑制視網膜血管新生作用,進一步的去研究,將來可能可以成為治療此類眼球血管新生性疾病的一種新方法。
綜合以上研究,我們發現了兩個重要的血管新生因子―fractalkine及Cyr61。我們利用了視網膜血管內皮細胞的細胞模式及不同的血管新生的動物模式去研究他們的血管新生作用。結果都顯示,這兩個因子為一種血管增生因子,且在眼球的血管新生作用上都參與了重要的步驟。fractalkine除了本身有血管增生作用外,它也會吸引單核球,經由發炎的機轉來引起眼球的血管新生。而Cyr61為CCN家族之一,它可以在組織或細胞缺氧下被誘發。Cyr61進一步的作用在內皮細胞的integrins受體時,可引起一連串的下游反應,最後引起血管新生。除此它也可能可以作用在纖維母細胞上,引起組織纖維化作用。而這兩種因子,在測得的增殖性糖尿病視網膜病變病患的玻璃體液中,都明顯的升高。這也進一步證實了這兩因子在此疾病上有其重要的角色。而且我們也發現了,Cyr61和重要的血管新生因子VEGF之間有協同及交互作用。最後,我們研究內皮細胞細胞膜上的integrins,利用來自蛇毒血清蛋白中的disintegrins試圖抑制血管新生作用,發現在細胞及動物模式中,disintegrins可以有效抑制血管新生。這也讓我們以後對於增殖性糖尿病視網膜病變這一類眼球血管新生作用治療的研發,有重要的突破。


Diabetic retinopathy is a common complication in patients of DM. Proliferative diabetic retinopathy (PDR) is the most common cause of blindness in DM patients. Several growth factors are involved in the pathogenesis of PDR, esp. VEGF. VEGF is a well-established factor and involved in the important pathogenesis of PDR. Although VEGF plays an important role in PDR, anti-VEGF therapy could not completely inhibit retinal angiogenesis in PDR and post-angiogenic fibrosis could not be inhibited. In addition to VEGF, several angogenic factors might be involved in retinal angiogenesis. We investigated the role of fractalkine (FKN), Cysteine-rich 61(Cyr61), and disintegrins in the pathogenesis of PDR.

Aim 1. Fractalkine, a CX3C chemokine, act as a mediator of ocular angiogenesis
Fractalkine (FKN) is a chemoattractant and adhesion molecule for leukocytes. Angiogenic effect of FKN also has been reported. We investigate FKN-mediated angiogenesis in vitro and in vivo to understand its role in ocular angiogenic disorders.
Fractalkine effects on cultured human umbilical vein endothelial cell (HUVEC) and bovine retinal capillary endothelial cell (BREC) were evaluated with chemotaxis assay and Matrigel capillary tube formation assay in vitro. Reverse transcriptase-polymerase chain reaction (RT-PCR) and Western blot analysis were used to detect mRNA and protein expression of FKN and its receptor, CX3CR1, in HUVEC and BREC. Rabbit corneal neovascularization assay and oxygen-induced retinopathy (OIR) model of mice were used to test the angiogenic property of FKN in vivo. Fractalkine levels of vitreous samples from proliferative diabetic retinopathy (PDR) patients were measured by enzyme-linked immunosorbent assay (ELISA). Immunodepletion of FKN in PDR vitreous samples by anti-FKN polyclonal antibody was observed in endothelial cells chemotaxis assays. Fractalkine significantly induced migration of HUVEC and BREC. Fractalkine induced formation of endothelial cell capillary tubes on Matrigel. Expression of FKN and CX3CR1 was detected in HUVEC and BREC by RT-PCR and Western blotting. Fractalkine significantly induced more blood vessel growth than control in rabbit corneal pocket neovascularization assay. Intravitreal injection of anti-mouse FKN antibody decreased retinal angiogenesis in the OIR model. Vitreous level of FKN was elevated in PDR patients as compared to control. Immunodepletion of soluble FKN from PDR vitreous samples caused 36.6% less migration of BREC. Take together, FKN is an angiogenic mediator in vitro and in vivo. Vitreous level of FKN was elevated in PDR patients. FKN may play an important role in ocular angiogenic disorders such as PDR.

Aim 2. Cysteine-rich 61, a member of CCN family, promotes retinal angiogenesis
Cysteine-rich 61 (Cyr61), a member of CCN family, is an angiogenic factor. We investigated Cyr61-mediated angiogenesis in vitro and in vivo to understand its role in ocular angiogenesis and diabetic retinopathy. Cyr61 effects on monkey chorioretinal endothelial cell (RF/6A) were evaluated using proliferation assay, chemotaxis assay, and Matrigel capillary tube formation assay in vitro. In addition, we investigated Cyr61 expression under hypoxic conditions by RT-PCR and Western blotting. A mouse model of oxygen-induced retinopathy (OIR) and a rat model of streptozocin-induced diabetes were used to test the angiogenic property of Cyr61 in vivo. Cyr61 levels were also measured in vitreous samples from proliferative diabetic retinopathy (PDR) patients by enzyme-linked immunosorbent assay (ELISA). Immunodepletion of Cyr61 in PDR vitreous samples by anti-Cyr61 polyclonal antibody was evaluated in an endothelial cells chemotaxis assay. Cyr61 significantly induced the proliferation and migration of RF/6A, and the formation of endothelial cell capillary tubes on Matrigel. Hypoxia significantly induced Cyr61 mRNA and protein expression Cyr61 was significantly expressed in neovascularized retina in the mouse OIR model and in the streptozocin-induced diabetic rat model. Intravitreal injection of anti-mouse Cyr61 antibody in the OIR model significantly suppressed retinal neovascularization. Vitreous levels of Cyr61 were elevated in PDR patients when compared with non-diabetic patients. Immunodepletion of Cyr61 from PDR vitreous samples significantly inhibited the migration of RF/6A cells. Cyr61 is an angiogenic mediator in vitro and in vivo. Vitreous levels of Cyr61 are elevated in PDR patients. Cyr61 may promote retinal angiogenesis, especially in PDR.

Aim 3. Elevation of cysteine-rich 61 levels in vitreous of patients with proliferative diabetic retinopathy
Cysteine-rich 61 (Cyr61) is one of angiogenic factors involved in proliferative diabetic retinopathy (PDR). To further investigate its role, we measure and compare the vitreous levels of Cyr61and vascular endothelial growth factor (VEGF) in patients with PDR and to localize Cyr61 expression in associated proliferative epiretinal membranes. Vitreous obtained from 56 patients with active PDR, 16 patients with active PDR pretreated with bevacizumab, 19 patients with quiescent PDR, 15 non-PDR (NPDR) patients with diabetic macular edema (DME) and 25 patients with other non-diabetic-related eye diseases, were subjected to enzyme-linked immunosorbent assay for Cyr61 and VEGF levels. Epiretinal membrane (ERM) from 6 patients with idiopathic ERMs, 5 patients with active PDR and 7 patients with active PDR pretreated with bevacizumab were stained immunohistochmically for Cyr61. Vitreous Cyr61 levels were significantly higher in active PDR patients than that in quiescent PDR patients, or nondiabetic control patients. Vitreous levels of Cyr61 were significantly elevated in NPDR patients with DME. The correlations between the vitreous levels of Cyr61 and the vitreous levels of VEGF were strong in active PDR, quiescent PDR, and DME groups. Pretreatment of bevacizumab significantly suppressed vitreous VEGF levels, however, did not inhibit vitreous Cyr61 levels in active PDR patients. Cyr61 was strongly detected in endothelial cells and myofibroblasts within active PDR membranes but not in idiopathic ERM. The localization of Cyr61 in myofibroblasts and endothelial cells suggests local autocrine-paracrine mechanism for induction of angiogenesis and post-angiogenic fibrosis in PDR.

Aim 4. Regulation of Cyr61/CCN1 expression by hypoxia through cooperation of c-Jun/AP-1 and HIF-1α in retinal vascular endothelial cells
Hypoxia is one of the major factors in the pathogenesis of diabetic retinopathy. Cysteine-rich 61 (Cyr61) is one of the angiogenic factors involved in the development of proliferative diabetic retinopathy (PDR). The aim of this study was to investigate the mechanism of hypoxia-induced Cyr61 expression in retinal vascular endothelial cells. The hypoxia-induced expression of mRNA and protein of Cyr61 was studied in monkey choroidal retinal vascular endothelial (RF/6A) cells. Luciferase reporter assays and electrophoretic mobility shift assays were used to identify the hypoxia responsible region and transcription factors in the Cyr61 promoter. Chromatin immunoprecipitation and immunoprecipitation assay were performed to study the role of hypoxia-inducible factor (HIF)-1α and c-Jun/AP-1 in Cyr61 transcriptional regulation. Hypoxia significantly induced Cyr61 mRNA and protein expression in RF/6A cells. The effect was mediated through phosphorylation of c-Jun. Luciferase assays, electrophoretic mobility shift assays, chromatin immunoprecipitation and immunoprecipitation showed that HIF-1α interacted with c-Jun/AP-1 and their binding on the AP-1 binding motif within the Cyr61 promoter induced the expression of Cyr61. The hypoxia induced transcriptional regulation of Cyr61, a hypoxia-inducible factor, in RF/6A cells was controlled by cooperation of HIF-1α and c-Jun/AP-1. Cyr61 may have an important role in ischemic retinal diseases, such as PDR.

Aim 5. Suppression of Ocular Neovascularization by Disintegrins Derived From Snake Venom
Integrins play an important role in the pathogenesis of angiogenesis. Recently, disintegrins derived from snake venom was showed to inhibit integrins-mediated angiogesis in oncology. We investigated the possibility that disintegrins inhibited angiogenesis in intraocular angiogenesis. Four disintegrins (GRGDS, Kistrin, Echistatin, and Flavoriden) were used to perform chemotaxis, matrigel tube formation, and adhesion assay in bovine retinal vascular endothelial cells (BRECs). Chemical injury-induced corneal neovascularization model was investigated the inhibition effect of disintegrins. To test the anti-angiogenic property in oxygen-induced retinopathy (OIR) model, intravitreal injection of disintegrins was performed to inhibit the in vivo angiogenesis. Vitreous samples of proliferative diabetic retinopathy (PDR) patients were collected during pars plana vitrectomy. Vitreous samples of PDR patients pretreated with disintegrins were used for chemotaxis assays to determine the role of disintegrins. Disintegrins significantly inhibited bFGF-induced migration, bFGF-induced tube formation, and adhesion in BRECs. Topical treatment of kistrin could inhibit chemical injury-induced corneal neovascularization of rats. Intravitreal injection of disintegrins significantly inhibited retinal neovascularization of mice in the OIR model. Vitreous samples from the PDR patients pretreated with disintegrins induced less migration of retinal endothelial cells. These results establish disintegrins derived from snake venom as an anti-angiogenic mediator in vitro and in vivo and suggest that these may play an important role in the ocular angiogenesis, such as PDR. It might be a new strategy for a new potential target for treating these diseases.
Take together, we found the two angiogenic factors, fractalkine and Cyr61, mediated as an important role in ocular angiogenesis. In the in-vitro and in-vivo experiments, we investigated the factors were important factors in ocular angiogenesis. Elevated vitreous levels of fractalkine and Cyr61 further proved their role in retinal angiogenesis. To further investigate the mechanism of Cyr61 expression, we found that hypoxia, an important fractor involved in PDR, could induce and regulate the transcription of the Cyr61 gene through cooperation of transcription factor HIF-1α and c-Jun/AP-1 in retinal vascular endothelial cells. Integrins mediated as important role in angiogenesis. Disintegrins derived from snake venom could effectively inhibit activation of integrins. We investigated the anti-angiogenic effect of disintegrins in ocular angiogenesis, and found that disintegrins could inhibit angiogenesis by inhibition of integrin activation through induction of apoptosis of endothelial cells. Therefore, these finding might give us a new strategy to treat ocular angiogenesis, esp. PDR.


口試委員會、指導教授與所長簽名表 I
國家圖書館碩博士論文授權書 II
誌謝 III
目錄 V
縮寫對照表 VIII
圖表目錄 X
中文摘要 1
英文摘要 8
一、緒論
1.1.糖尿病視網膜病變介紹及其重要性: 14
1.1.1視網膜介紹: 14
1.1.2. 糖尿病視網膜病變流行病學及文獻回顧 15
1.1.3糖尿病網膜病變的臨床表現 17
1.1.4.糖尿病視網膜病變的診斷 21
1.1.5.糖尿病視網膜病變危險因子介紹及文獻回顧 22
1.1.6.糖尿病視網膜病變治療 23
1.1.7. 糖尿病視網膜病變致病機轉及文獻回顧 24
1.1.8.糖尿病視網膜病變新治療 26
1.1.8.1內科病情控制 26
1.1.8.2藥物治療 26
1.1.9視網膜血管新生因子介紹及文獻回顧 27
1.1.10. 增殖性糖尿病視網膜病變治療上尚未解決的問題及文獻回顧 29
1.1.11. 研究第一部份: Fractalkine在眼球血管新生性疾病之研究 31
1.1.11.1.研究問題之動機及重要性與文獻探討 31
1.1.11.2. 欲研究問題之假說與特定目的 32
1.1.12 研究第二部份: Cysteine-rich 61在增生性糖尿病視網膜病變的致病機轉上扮演重要角色之研究 33
1.1.12.1. 研究問題之動機及重要性與文獻探討 33
1.1.12.2. 欲研究問題之假說與特定目的 35
1.1.13. 研究第三部份: 增殖性糖尿病視網膜病變病人玻璃體內Cyr61濃度測定和危險因子分析、及在增生視網膜前纖維膜Cyr61表現之研究 35
1.1.13.1. 研究問題之動機及重要性與文獻探討 35
1.1.13.2. 欲研究問題之假說與特定目的 36
1.1.14. 研究第四部份: 視網膜血管內皮細胞在缺氧環境下引發Cyr61表現之機轉研究 37
1.1.14.1. 研究問題之動機及重要性與文獻探討 37
1.1.14.2.欲研究問題之假說與特定目的 38
1.1.15. 研究第五部份: 蛇毒血清蛋白在眼球血管新生作用之研究 38
1.1.15.1. 研究問題之動機及重要性與文獻探討 38
1.1.15.2.欲研究問題之假說與特定目的 42
二、方法
2.1. Fractalkine在眼球血管新生性疾病之研究 43
2.2. Cysteine-rich 61在增生性糖尿病視網膜病變的致病機轉上扮演重要角色之研究 52
2.3. 增殖性糖尿病視網膜病變病人玻璃體內Cyr61濃度測定和危險因子分析、及在增生視網膜前纖維膜Cyr61表現之研究 56
2.4視網膜血管內皮細胞在缺氧環境下引發Cyr61表現之機轉研究 59
2.5. 蛇毒血清蛋白在眼球血管新生作用之研究 67
三、結果
3.1. Fractalkine在眼球血管新生性疾病之研究 71
3.2. Cysteine-rich 61在增生性糖尿病視網膜病變的致病機轉上扮演重要角色之研究 75
3.3. 增殖性糖尿病視網膜病變病人玻璃體內Cyr61濃度測定和危險因子分析、及在增生視網膜前纖維膜Cyr61表現之研究 79
3.4視網膜血管內皮細胞在缺氧環境下引發Cyr61表現之機轉研究 82
3.5. 蛇毒血清蛋白在眼球血管新生作用之研究 85
四、討論
4.1. Fractalkine在眼球血管新生性疾病之研究 88
4.2. Cysteine-rich 61在增生性糖尿病視網膜病變的致病機轉上扮演重要角色之研究 91
4.3增殖性糖尿病視網膜病變病人玻璃體內Cyr61濃度測定和危險因子分析、及在增生視網膜前纖維膜Cyr61表現之研究 94
4.4視網膜血管內皮細胞在缺氧環境下引發Cyr61表現之機轉研究 97
4.5. 蛇毒血清蛋白在眼球血管新生作用之研究 100
五、展望
5.1. Fractalkine在眼球血管新生性疾病之研究 103
5.2. Cysteine-rich 61在增生性糖尿病視網膜病變的致病機轉上扮演重要角色之研究 105
5.3. 增殖性糖尿病視網膜病變病人玻璃體內Cyr61濃度測定和危險因子分析、及在增生視網膜前纖維膜Cyr61表現之研究 107
5.4視網膜血管內皮細胞在缺氧環境下引發Cyr61表現之機轉研究 109
5.5. 蛇毒血清蛋白在眼球血管新生作用之研究 111
六、論文英文簡述 113
七、參考文獻 124
八、圖表 145
九、附錄: 188


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