本文關(guān)鍵詞： AGEs RAGE LTP 信號(hào)通路　出處：《蘭州大學(xué)》2014年碩士論文　論文類型：學(xué)位論文

【摘要】：突觸的退化是老齡化及老齡化相關(guān)疾病(包括老年癡呆AD)的早期特征。糖代謝終末產(chǎn)物-AGEs的積累與老齡化有關(guān),蛋白質(zhì)或脂類非酶糖基化(或者氧化)反應(yīng)形成AGEs的初級(jí)產(chǎn)物,之后,逐漸積累形成AGEs。尤其對(duì)糖尿病、AD患者,體內(nèi)血糖的持高和神經(jīng)退化進(jìn)一步加速了AGEs形成,影響大腦神經(jīng)系統(tǒng),導(dǎo)致細(xì)胞功能紊亂。RAGE,即AGEs的受體,它是細(xì)胞表面分子免疫球蛋白超家族成員,同時(shí)也是目前研究最多,AGEs與RAGE相互作用,引發(fā)多種疾病。 本論文研究神經(jīng)RAGE基因缺失對(duì)AGEs誘導(dǎo)突觸損傷的保護(hù)機(jī)理。我們以野生型小鼠(WT)作為參照,選用RAGE基因全身敲除(RKO),大腦神經(jīng)中樞敲除RAGE基因(NRKO),神經(jīng)元內(nèi)端RAGE基因缺失(DN-RAGE)的三種轉(zhuǎn)基因小鼠,通過(guò)以下方法進(jìn)行對(duì)比研究：(1)利用電生理技術(shù)檢測(cè)小鼠海馬CA1區(qū)的LTP；(2)利用抗原抗體反應(yīng),采用熒光免疫技術(shù)表征組織或細(xì)胞內(nèi)抗原物質(zhì),對(duì)海馬區(qū)的腦片、相應(yīng)神經(jīng)元染色,最后由共聚焦顯微鏡判定；(3)借助凝膠層析法分析AGEs相應(yīng)蛋白(如RAGE、P38, ERK, GSK, JNK等)的表達(dá)強(qiáng)弱。上述幾種表征方法所得實(shí)驗(yàn)結(jié)果是一致的,我們可以確定：AGEs的受體-RAGE缺失,可以規(guī)避AGEs與RAGE結(jié)合對(duì)LTP的損害及減少突觸數(shù)量。此外,我們還嘗試多種相應(yīng)蛋白(例如P38, ERK, GSK, JNK等)及蛋白抑制劑,進(jìn)一步研究AGEs與受體RAGE的信號(hào)通路,最終確定P38蛋白在AGEs誘導(dǎo)突觸損傷中起到了介導(dǎo)作用。 實(shí)驗(yàn)結(jié)果顯示神經(jīng)受體蛋白R(shí)AGE是AGEs引發(fā)突觸功能紊亂的信號(hào)傳感器。由此,我們發(fā)現(xiàn)了AGEs導(dǎo)致突觸受損的新機(jī)制：AGEs與受體RAGE結(jié)合,激活神經(jīng)蛋白P-38打開信號(hào)通路進(jìn)而導(dǎo)致突觸損傷；所以,阻止受體RAGE與其配體的結(jié)合,可以作為治療老年相關(guān)神經(jīng)疾病的一個(gè)靶點(diǎn)。
[Abstract]:Synaptic degeneration is an early feature of aging and age-related diseases, including Alzheimer's disease (AD). The accumulation of AGEs, the end product of glucose metabolism, is associated with aging. Nonenzymatic glycosylation (or oxidation) of proteins or lipids forms the primary product of AGEs, and then accumulates to form ages, especially in AD patients with diabetes mellitus. The hyperglycemia and neurodegeneration in vivo further accelerate the formation of AGEs, affect the brain nervous system, and lead to cell dysfunction. RAGE, the receptor of AGEs. It is a member of the cell surface molecular immunoglobulin superfamily, and it is also the most studied interaction between ages and RAGE, which causes many diseases. In this study, we studied the protective mechanism of neural RAGE gene deletion on synaptic injury induced by AGEs. We selected RAGE gene knockout as a reference for wild-type mice. Three kinds of transgenic mice with RAGE gene knockout and RAGE gene deletion at the inner end of the neuron (DN-RAGE). The electrophysiological technique was used to detect the CA1 in the hippocampus of mice. (2) the antigen-antibody reaction was used to characterize the antigens in tissues or cells by fluorescence immunoassay, and the corresponding neurons were stained in the brain slices of the hippocampus, which were finally determined by confocal microscopy. The corresponding proteins of AGEs (such as Rage P38, ERK, GSK) were analyzed by gel chromatography. The results of the above methods are consistent. We can confirm the deletion of the receptor-rage of 1% ages. We can avoid the damage caused by AGEs and RAGE binding to LTP and reduce the number of synapses. In addition, we try a variety of corresponding proteins (such as P38, ERK, GSK). JNK et al.) and protein inhibitors to further study the signaling pathway between AGEs and receptor RAGE, and finally confirm that P38 protein plays a mediating role in AGEs induced synaptic injury. The results show that the neural receptor protein RAGE is a signal sensor of synaptic dysfunction induced by AGEs. We have found a new mechanism of synaptic damage caused by AGEs: Ages binding to receptor RAGE, activating neuroprotein P-38 to open signal pathway and leading to synaptic injury. Therefore, blocking the binding of receptor RAGE to its ligand may be a target for the treatment of geriatric neuropathies.
【學(xué)位授予單位】：蘭州大學(xué)
【學(xué)位級(jí)別】：碩士
【學(xué)位授予年份】：2014
【分類號(hào)】：R741

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相關(guān)期刊論文 前2條

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本文編號(hào)：1466506