本文選題：阿爾茨海默病模型 + 獼猴��； 參考：《中國科學(xué)技術(shù)大學(xué)》2014年碩士論文

【摘要】：阿爾茨海默病(Alzheimer's disease,D)是一種以老年斑和神經(jīng)纖維纏結(jié)為主要病理特征的神經(jīng)退行性腦疾病。關(guān)于AD的發(fā)病機(jī)制,兩個(gè)最有影響力的假說是淀粉樣蛋白(myloid β, Aβ)級(jí)聯(lián)假說和tau蛋白假說。AD多起病于老年期,AD病人認(rèn)知功能進(jìn)行性丟失,以記憶損害為早期表現(xiàn)。被確診后的AD患者,剩余的存活期平均約只有5.7年,并且患者發(fā)病后一直需要有人照顧,后期生活不能自理。AD患病人數(shù)已經(jīng)超過2600萬且在逐漸增多,給家庭和社會(huì)帶來重大的經(jīng)濟(jì)和精神負(fù)擔(dān)。AD至今無有效的治療方法,而基于AD小鼠模型開發(fā)的許多藥物的臨床試驗(yàn)失敗。獼猴與人類親緣關(guān)系更近,并且在老年獼猴腦中發(fā)現(xiàn)存在Ap斑塊。因此建立能反應(yīng)AD病程的有效獼猴模型,探索AD的疾病機(jī)理,并尋找有效的診斷和治療方法,既具有重大的科學(xué)意義,又是亟待解決的科學(xué)難題。 我們實(shí)驗(yàn)室擬采用向獼猴大腦皮層注射攜帶家族性AD基因的病毒或體外合成并培養(yǎng)的纖維化Aβ42的方法,來建立AD獼猴模型。建模的兩個(gè)關(guān)鍵準(zhǔn)備工作是：1)篩選合適的病毒載體,為下一步的轉(zhuǎn)基因工作做準(zhǔn)備；2)建立一套新型認(rèn)知檢測系統(tǒng),用來對獼猴實(shí)驗(yàn)處理前后的學(xué)習(xí)記憶能力進(jìn)行評(píng)價(jià)。這兩部分工作構(gòu)成了本論文的主要內(nèi)容。 病毒篩選方面,根據(jù)國內(nèi)外文獻(xiàn),我們嘗試了慢病毒和腺相關(guān)病毒(AdenoAssociated Virus,AAV),總共有15種。在獼猴腦中只有AAV2和AAV2/9這兩種病毒有表達(dá),而對照實(shí)驗(yàn)在大鼠腦中只有攜帶Swedish/Dutch/London AD基因的慢病毒、AAV2/8、AAV2和AAV2/9,這四種病毒有表達(dá),在此基礎(chǔ)上我們還摸索出一種合適的病毒注射方法。在獼猴認(rèn)知系統(tǒng)建立方面,我們建立了一套獼猴自由活動(dòng)情況下,觸摸屏認(rèn)知自動(dòng)綜合測試新型系統(tǒng)。這套系統(tǒng)在國內(nèi)屬于首創(chuàng)。該系統(tǒng)實(shí)現(xiàn)了4種測試軟件,主要用來測試獼猴空間和非空間的工作記憶能力。軟件中的視覺空間學(xué)習(xí)測試,已有三只獼猴學(xué)會(huì)了,并都做滿了1000個(gè)任務(wù)。此外,我們還開發(fā)了一套較好的獼猴訓(xùn)練方法。所有的努力為建立AD獼猴模型奠定了重要的基礎(chǔ)。
[Abstract]:Alzheimer's disease (Alzheimer's disease) is a neurodegenerative brain disease characterized by senile plaques and neurofibrillary tangles. About the pathogenesis of AD, the two most influential hypotheses are the amyloid 尾 (A 尾) cascade hypothesis and the tau protein hypothesis. After being diagnosed with AD, the remaining survival time is only about 5.7 years on average, and the patient has been in need of care since the onset of the disease. The number of AD patients who cannot take care of themselves in later life has exceeded 26 million and is gradually increasing. A significant economic and psychological burden on families and society. There is no effective treatment for AD, and many drugs based on AD mouse models have failed in clinical trials. Rhesus monkeys are more closely related to humans, and Ap plaques are found in the brains of old rhesus monkeys. Therefore, it is of great scientific significance to establish an effective rhesus monkey model that can reflect the course of AD, to explore the disease mechanism of AD, and to find effective diagnosis and treatment methods. We intend to establish a rhesus monkey model by injecting virus carrying familial AD gene or fibrotic A 尾 42 synthesized and cultured in vitro into the cerebral cortex of rhesus mulatta. The two key preparations for modeling are: 1) screening appropriate virus vectors and preparing for the next step of transgenic work A) A new cognitive detection system is established to evaluate the learning and memory ability of rhesus monkeys before and after experimental treatment. These two parts of the work constitute the main content of this paper. In the aspect of virus screening, according to the domestic and foreign literature, we have tried lentivirus and adeno-associated virus AAVA, there are 15 species in total. Only AAV2 and AAV2/9 were expressed in the brain of rhesus monkeys, while in the control experiment, there were only two lentiviruses, AAV2 / 8 AAV2 and AAV2 / 9, which carried Swedish/Dutch/London AD gene in the brain of rats. On the basis of this, we found a suitable method of virus injection. In the aspect of rhesus monkey cognitive system, we set up a new system for the automatic test of Rhesus monkey's cognition under the condition of free movement of Rhesus mulatta (Rhesus mulatta). This system is the first in China. The system implements four kinds of testing software, mainly used to test the spatial and non-spatial working memory ability of rhesus monkey. In the software, three macaques have learned to learn the visual space and have done 1000 tasks. In addition, we have also developed a better training method for rhesus monkeys. All these efforts have laid an important foundation for the establishment of AD rhesus monkey model.
【學(xué)位授予單位】：中國科學(xué)技術(shù)大學(xué)
【學(xué)位級(jí)別】：碩士
【學(xué)位授予年份】：2014
【分類號(hào)】：R749.16

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本文編號(hào)：1818045