本文選題：YF-452 + 血管新生��； 參考：《華東師范大學(xué)》2014年碩士論文

【摘要】：血管新生是一個復(fù)雜的過程,包括內(nèi)皮細(xì)胞的增殖、遷移、突破基底膜并形成三維管狀網(wǎng)絡(luò),它是機(jī)體生長發(fā)育過程中必不可少的過程。同時,血管新生在疾病的發(fā)生發(fā)展中也發(fā)揮著重要的作用,尤其是腫瘤。新的血管生長進(jìn)入腫瘤內(nèi)部,為其提供必需的氧氣和營養(yǎng)物質(zhì),從而為腫瘤的生長和轉(zhuǎn)移提供了便利條件。因此,抑制血管新生被認(rèn)為是抗腫瘤的重要療法之一。由于腫瘤細(xì)胞基因組不穩(wěn)定容易突變而產(chǎn)生耐藥性,所以和傳統(tǒng)的靶向于腫瘤細(xì)胞的化療相比,抗血管新生治療呈現(xiàn)出一定的優(yōu)勢。血管新生受多種刺激因子和抑制因子的嚴(yán)格調(diào)控。其中VEGF在眾多促血管新生的生長因子和細(xì)胞因子中,對腫瘤血管新生的調(diào)控起著重要作用且在腫瘤組織中高表達(dá)。VEGF通過與內(nèi)皮細(xì)胞表面的受體結(jié)合發(fā)揮其生物學(xué)功能,即VEGFR1(Flt-1),負(fù)責(zé)細(xì)胞的有絲分裂和化學(xué)應(yīng)答；VEGFR2(KDR/Flk-1)負(fù)責(zé)內(nèi)皮細(xì)胞的形態(tài)發(fā)生。VEGFR2的激活導(dǎo)致下游多種胞內(nèi)信號分子的激活,包括Src家族激酶,FAK、ERK以及PI3K/AKT激酶等,它們分別調(diào)控血管滲透性,促進(jìn)內(nèi)皮細(xì)胞的增殖、遷移和分化,并維持細(xì)胞的存活。因此,VEGFR2和這些胞內(nèi)信號分子被認(rèn)為是抑制腫瘤血管新生的重要靶點(diǎn)。目前,臨床上已有多種VEGFR2的抑制劑用于治療腫瘤。但是,近年來臨床結(jié)果顯示,大多數(shù)這些抗癌藥物呈現(xiàn)出明顯的副反應(yīng)且價格比較昂貴,所以尋找新的具有自主知識產(chǎn)權(quán)的小分子血管新生抑制劑作為抗癌備選藥物具有重要意義。本研究中,我們通過對實驗室小分子化合物庫中的藥物進(jìn)行篩選,得到一個小分子化合物YF-452并分析其在體外對內(nèi)皮細(xì)胞的抑制效果。同時在體內(nèi)模型中也檢測了YF-452的活性并對它抑制血管新生的分子機(jī)制進(jìn)行了探索。YF-452在體外能夠明顯抑制內(nèi)皮細(xì)胞的遷移、侵襲和管狀網(wǎng)絡(luò)的形成。半體內(nèi)大鼠胸主動脈環(huán)模型和兩個體內(nèi)模型(雞胚尿囊膜模型和小鼠角膜微囊袋模型)也顯示出YF-452能夠顯著抑制新生微血管的形成。通過進(jìn)一步的研究發(fā)現(xiàn),YF-452能夠抑制小鼠異種移植模型中腫瘤的生長及瘤內(nèi)血管新生,和對照組相比,小鼠注射4Omg/kg/d YF-452對腫瘤生長的抑制率達(dá)到70%。通過對腫瘤組織CD31免疫熒光染色也表明YF-452具有抗血管新生功能。同時對各組小鼠的組織器官切片進(jìn)行HE染色,并未發(fā)現(xiàn)有明顯的病理學(xué)改變,各組小鼠的體重也未發(fā)生明顯的變化,說明YF-452在抑制腫瘤生長和血管新生的過程中并未產(chǎn)生明顯的毒性。Western Blot結(jié)果顯示YF-452能夠抑制VEGF誘導(dǎo)的VEGFR2的活性及下游蛋白激酶Src、FAK、ERK的激活。綜上所述,我們找到了一個潛在的小分子化合物YF-452,能通過靶向VEGFR2的激活抑制血管新生,并將有可能成為腫瘤治療的備選藥物。此外,我們還建立了高脂飲食+STZ誘導(dǎo)的II型糖尿病小鼠模型,并在此基礎(chǔ)上建立了糖尿病小鼠后肢缺血模型和傷口愈合模型,用于我課題組另外一名同學(xué)關(guān)于治療糖尿病并發(fā)癥新藥研究,為藥物療效的評價奠定基礎(chǔ)。
[Abstract]:Angiogenesis is a complex process, including the proliferation, migration, breakthrough of the basement membrane and the formation of a three-dimensional tubular network. It is an essential process in the growth and development of the body. At the same time, angiogenesis is also playing an important role in the development of the disease, especially the tumor. It provides the necessary oxygen and nutrients to facilitate the growth and metastasis of the tumor. Therefore, inhibition of angiogenesis is considered to be one of the most important therapies for anti-tumor. New treatment presents certain advantages. Angiogenesis is regulated by a variety of stimulating factors and inhibitory factors. Among them, VEGF plays an important role in the regulation of neovascularization of neovascularization and the high expression of.VEGF in tumor tissues by binding to receptors on the surface of endothelial cells. Its biological function, VEGFR1 (Flt-1), is responsible for the mitosis and chemical response of cells; VEGFR2 (KDR/Flk-1) is responsible for the activation of.VEGFR2 in the morphology of endothelial cells leading to the activation of a variety of intracellular signaling molecules downstream, including Src family kinase, FAK, ERK, and PI3K/ AKT kinases, which regulate vascular permeability and promote endothelial refinement, respectively. The proliferation, migration and differentiation of cells and the survival of the cells are maintained. Therefore, VEGFR2 and these intracellular signaling molecules are considered as an important target for inhibition of neovascularization. At present, a variety of VEGFR2 inhibitors have been used in the treatment of tumors. However, in recent years, clinical results show that most of these anticancer drugs present obvious side reactions. It is of great importance to find a new small molecular vascular neoplastic inhibitor with independent intellectual property as an anticancer drug. In this study, we screened a small molecule compound YF-452 by screening the drugs in the laboratory small molecule compound library and analyzed its effect on endothelial cells in vitro. At the same time, the activity of YF-452 was also detected in the body model and its molecular mechanism of inhibiting angiogenesis was explored..YF-452 could inhibit endothelial cell migration, invasion and formation of tubular network in vitro. The rat thoracic aorta ring model and two individual internal model (chicken embryo allantoic membrane model and mouse model in vivo) The corneal microcapsule model also showed that YF-452 could significantly inhibit the formation of neovascularization. Through further study, YF-452 could inhibit the growth of tumor and the angiogenesis in the xenotransplantation model in mice. Compared with the control group, the inhibition rate of 4Omg/kg/d YF-452 on tumor growth in mice was 70%. through the tumor group. CD31 immunofluorescence staining also showed that YF-452 had anti angiogenic function. At the same time, the tissues and organs of each group were stained with HE, and no obvious pathological changes were found. The weight of mice in each group did not change obviously. It showed that YF-452 did not produce obvious poison in the process of inhibiting tumor growth and angiogenesis. The results of sex.Western Blot show that YF-452 can inhibit the activity of VEGFR2 induced by VEGF and the activation of the downstream protein kinase Src, FAK, ERK. In summary, we have found a potential small molecule compound YF-452, which can inhibit angiogenesis by targeting VEGFR2, and will be a candidate for cancer treatment. In addition, we also A model of II induced diabetic mice induced by high fat diet +STZ was established. On this basis, the hind limb ischemia model and wound healing model of diabetic mice were established, which was used for the study of new drugs for diabetic complications in the other class of our group, laying a foundation for the evaluation of the efficacy of the drug.
【學(xué)位授予單位】：華東師范大學(xué)
【學(xué)位級別】：碩士
【學(xué)位授予年份】：2014
【分類號】：R96

【相似文獻(xiàn)】

相關(guān)碩士學(xué)位論文 前1條

1 劉永瑞;小分子化合物YF-452抑制血管新生的功能及機(jī)理研究[D];華東師范大學(xué);2014年

，

本文編號：2083516