本文選題：急性缺血性卒中　切入點(diǎn)：血管新生　出處：《北京協(xié)和醫(yī)學(xué)院》2016年博士論文　論文類(lèi)型：學(xué)位論文

【摘要】：背景：腦卒中已經(jīng)在全球范圍內(nèi)成為導(dǎo)致死亡以及長(zhǎng)期殘疾的首要病因之一,因而尋找并發(fā)展新型有效的治療缺血性卒中的方法顯得至關(guān)重要。近年來(lái),多項(xiàng)研究顯示缺血性卒中發(fā)生后病灶部位的血管新生不僅能夠提高局部的血供,同時(shí)也促進(jìn)內(nèi)源性的神經(jīng)再生并且有助于卒中后的神經(jīng)功能恢復(fù),因此,血管新生已經(jīng)成為缺血性卒中治療的研究熱點(diǎn)。人尿激肽原酶(即注射用尤瑞克林),作為國(guó)內(nèi)近年來(lái)開(kāi)發(fā)的Ⅰ類(lèi)新藥,臨床試驗(yàn)已經(jīng)證實(shí)其能夠減少急性缺血性卒中患者的神經(jīng)功能損傷,并提高遠(yuǎn)期預(yù)后；但關(guān)于人尿激肽原酶是否能夠促進(jìn)病灶部位的血管新生,目前的研究還比較少。68Ga-PRGD2 PET/CT作為一項(xiàng)能夠特異性識(shí)別新生血管表面的整合素αvβ3受體、從而評(píng)估機(jī)體血管新生狀況的無(wú)創(chuàng)的分子靶向顯影技術(shù),是目前新生血管顯像研究的重要內(nèi)容,并已在腫瘤、心肌梗死等疾病中得到應(yīng)用,但將其應(yīng)用于評(píng)估卒中后缺血灶血管新生的研究尚且較少。目的：1、評(píng)估68Ga-PRGD2 PET顯影技術(shù)應(yīng)用于大鼠大腦中動(dòng)脈卒中(MCAO)模型中檢測(cè)血管新生狀況的可行性；2、結(jié)合分子影像學(xué)及生物學(xué)指標(biāo)綜合評(píng)估人尿激肽原酶(注射用尤瑞克林)對(duì)大鼠MCAO模型是否具有血管新生作用。方法：通過(guò)線栓法建立SD大鼠大腦中動(dòng)脈卒中(MCAO)模型,將建模成功的大鼠分為①尤瑞克林給藥組：通過(guò)靜脈注射3.5×10-3PNA/(kg·d),療程分為7天和14天；②對(duì)照組：通過(guò)腹腔注射等量生理鹽水,療程同樣分為7天和14天。另選擇健康SD大鼠組成假手術(shù)組,通過(guò)腹腔注射等量生理鹽水,療程分為7天和14天。對(duì)尤瑞克林給藥組和對(duì)照組大鼠進(jìn)行以下方面的評(píng)價(jià)：①建模后第1、3、7、14天行Longa評(píng)分評(píng)估神經(jīng)功能恢復(fù)情況;②在建模后第7、14天分別完成18F-FDG MicroPET和68Ga-PRGD2 MicroPET檢查；③在建模后第7、14天分別取給藥組、對(duì)照組大鼠患側(cè)大腦皮層病灶周邊組織通過(guò)Western Blot法檢測(cè)整合素β3水平；④在建模后第7天、14天分別取給藥組、對(duì)照組和假手術(shù)組大鼠右側(cè)大腦皮層病灶周邊組織通過(guò)ELISA法檢測(cè)VEGF-A水平。結(jié)果：1、建模后第1、3、7天給藥組及對(duì)照組大鼠Longa評(píng)分均無(wú)顯著性差異,建模后第14天給藥組Longa評(píng)分較對(duì)照14天組降低,提示給藥組可能有神經(jīng)功能恢復(fù)更好的趨勢(shì),但差異不具有統(tǒng)計(jì)學(xué)意義(P=0.06)；2、18F-FDG MicroPET顯像提示給藥和對(duì)照7天組大鼠患側(cè)大腦均可見(jiàn)代謝明顯減低區(qū),兩組間放射性攝取無(wú)顯著性差異(P0.05),給藥14天組大鼠放射性攝取比對(duì)照14天組有升高的趨勢(shì),但兩組間無(wú)顯著性差異(P=0.051),給藥14天組與7天組相比放射性攝取無(wú)顯著性差異(P0.05)；3、68Ga-PRGD2 MicroPET顯像提示給藥7天組、給藥14天組大鼠梗死區(qū)放射性攝取均較對(duì)照7天組、對(duì)照14天組升高(P0.05),給藥14天組攝取值與給藥7天組相比無(wú)顯著性差異(P0.05)；4、Western Blot檢測(cè)結(jié)果顯示給藥7天組患側(cè)腦組織整合素β3水平高于對(duì)照7天組(P0.05),給藥14天組與對(duì)照14天組整合素β3水平無(wú)顯著性差異(P0.05)；5、ELISA檢測(cè)顯示給藥7天及14天組大鼠腦組織VEGF-A水平均高于對(duì)照7天及14天組(P0.05),給藥14天組大鼠腦組織VEGF-A水平較給藥7天組無(wú)顯著性差異(P0.05)。結(jié)論：1、人尿激肽原酶(注射用尤瑞克林)對(duì)MCAO大鼠具有促進(jìn)血管新生的作用,并可能對(duì)改善急性缺血性卒中后的神經(jīng)功能恢復(fù)發(fā)揮一定的作用：2、68Ga-PRGD2 MicroPET可以顯示血管新生空間分布,用于實(shí)驗(yàn)動(dòng)物缺血性卒中后血管新生的評(píng)估具有一定價(jià)值,需要擴(kuò)大研究以進(jìn)一步證實(shí)。
[Abstract]:Background: stroke has become one of the leading causes of death and long-term disability worldwide, and therefore look for method for the development of new and effective treatment of ischemic stroke is crucial. In recent years, many studies have shown that ischemic stroke occurred after lesion of angiogenesis can not only improve the local blood supply, but also promote the recovery of endogenous. The nerve regeneration and contribute to the neurological function after stroke. Therefore, angiogenesis has become a hot topic in the treatment of ischemic stroke. Urinary kallikerein (Urinary Kallidinogenase for Injection), as a new drug developed in recent years in China, clinical trials have confirmed that it can reduce the neurological damage in patients with acute ischemic stroke, and improve long term prognosis; but about human urinary kallikrein whether lesion can promote angiogenesis, the present study also compared .68Ga-PRGD2 PET/CT as a specific recognition of neovascular surface integrin alpha v beta 3 receptor, to evaluate the angiogenesis status of body without a molecular target to the developing technology, is the important content of angiogenesis imaging research, and has been applied in tumor, myocardial infarction and other diseases, but its application the new evaluation on vascular ischemia after stroke research even less. Objective: To evaluate 68Ga-PRGD2 1, PET imaging technology applied in rats with middle cerebral artery stroke (MCAO) the feasibility of detecting angiogenesis in the model; 2, combined with molecular imaging and comprehensive assessment of biological indicators of human urinary kallikrein (Urinary Kallidinogenase for Injection) to whether the rat model of MCAO with angiogenesis. Methods: a SD rat model of middle cerebral artery stroke by suture method (MCAO) model, the successful model rats were divided into the Yuri Franklin administration Group by intravenous injection of 3.5 * 10-3PNA/ (kg - D). The course is divided into 7 days and 14 days; the control group by intraperitoneal injection of saline, treatment is also divided into 7 days and 14 days. The other healthy SD rats were selected consisting of sham operation group by intraperitoneal injection of saline, treatment for 7 days and 14 days. Yuri Klein on treatment group and evaluate the rats in control group: 1,3,7,14 day Longa score to assess the recovery of nerve function after the modeling; modeling in 7,14 days after the completion of 18F-FDG MicroPET and 68Ga-PRGD2 MicroPET were examined in the model; after 7,14 days respectively the medicine group, the control group rat ipsilateral cerebral cortex tissue surrounding the lesions detected by Western Blot method 3 integrin beta level; the seventh day 14 days after modeling, respectively treatment group, control group and sham operation group rats with right cerebral cortex lesions surrounding tissue by E Detection of VEGF-A level by LISA. Results: 1. The modeling of 1,3,7 days after treatment group and control group Longa rats were no significant difference between the model fourteenth days after the treatment group Longa score than the control group decreased 14 days, suggesting that the drug group may have better neurological recovery trend, but the difference is not statistical significance (P=0.06); 2,18F-FDG MicroPET imaging suggest that treatment and control group of 7 day rat ipsilateral brain showed significantly lower metabolism, uptake between the two groups had no significant difference (P0.05), administered 14 days group uptake in rats than in the control group of 14 days has increased, but the two groups there is no significant difference between (P=0.051), administered 14 days group and 7 days group compared uptake had no significant difference (P0.05); 3,68Ga-PRGD2 MicroPET imaging that administered 7 days group, administered 14 days group infarction rats uptake were lower than those in the control group of 7 days, 14 days in control group increased (P0 .05), administered 14 days group uptake value compared with medication for 7 days showed no significant difference (P0.05); 4, Western Blot showed that the administration of 7 days group ipsilateral brain tissue integrin beta 3 was higher than the control group for 7 days (P0.05), administered 14 days group and the control group of 14 days integrin beta 3 level no significant difference (P0.05); 5, ELISA showed that the administration of 7 days and 14 days group VEGF-A level in brain tissue of rats was higher than that of the control group 7 days and 14 days (P0.05), administered 14 days group VEGF-A level in brain tissue of rats were administered for 7 days were no significant the difference (P0.05). Conclusion: 1, human urinary kallidinogenase (Urinary Kallidinogenase for Injection) can promote angiogenesis of MCAO rats, and may improve the neurological function after acute ischemic stroke recovery play a role: 2,68Ga-PRGD2 MicroPET can show the distribution of angiogenesis in space, is used to evaluate the angiogenesis of ischemic animal experiment after stroke There is a certain value that needs to be expanded to be further confirmed.

【學(xué)位授予單位】：北京協(xié)和醫(yī)學(xué)院
【學(xué)位級(jí)別】：博士
【學(xué)位授予年份】：2016
【分類(lèi)號(hào)】：R743.3

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