本文關(guān)鍵詞：NgR和NEP1-35結(jié)合小肽的設(shè)計(jì)篩選及其促中樞神經(jīng)再生研究　出處：《第三軍醫(yī)大學(xué)》2006年博士論文　論文類型：學(xué)位論文

  更多相關(guān)文章： 中樞神經(jīng)系統(tǒng) 損傷 再生 Nogo-66 NgR 噬菌體隨機(jī)肽庫(kù)

【摘要】： 成年哺乳動(dòng)物中樞神經(jīng)系統(tǒng)(central nervous system,CNS)損傷后難以再生,其結(jié)果就是某些功能的永久性喪失。而周圍神經(jīng)系統(tǒng)(peripheral nervous system,PNS)損傷后可以再生,并且在功能上也能得到較好的恢復(fù)。但是在受損的CNS部位移植胚胎周圍神經(jīng)組織等,卻能觀察到明顯的再生現(xiàn)象,這提示CNS并非缺乏再生能力,而是損傷后的局部微環(huán)境中存在對(duì)再生不利的因素。目前已知,在CNS髓鞘中存在多種突起再生抑制性分子,如Nogo、髓鞘相關(guān)糖蛋白(myelin associated glycoprotein,MAG),少突膠質(zhì)細(xì)胞相關(guān)糖蛋白(oligodendrocyte myelin associated glycoprotein,OMgp )等。為克服髓鞘抑制分子的作用,研究者們嘗試了多種不同的方法,如,使用抗Nogo-A抗體IN-1,敲除Nogo基因和使用Nogo分子拮抗劑等,但是都沒有取得非常令人滿意的效果。近年來(lái)的研究發(fā)現(xiàn)Nogo有三種亞型,分別為Nogo-A、B和C,它們的C-末端高度同源,包括兩個(gè)跨膜域和一個(gè)短的胞外環(huán)狀結(jié)構(gòu)(Nogo-66)。而在CNS中發(fā)揮抑制作用的亞型為Nogo-A,根據(jù)其發(fā)揮功能的途徑可以分為amino-Nogo和Nogo-66兩個(gè)部分。有趣的是OMgp、MAG和Nogo-A雖然在序列上沒有相似性,但是卻可以通過同一個(gè)受體NgR來(lái)傳遞信號(hào),這也許是它們?cè)诳臻g結(jié)構(gòu)上的相似性造成的結(jié)果。NgR沒有胞內(nèi)結(jié)構(gòu),只能通過共受體向下傳遞信號(hào),RhoA是這條信息傳導(dǎo)通路上的重要分子,直接或間接增強(qiáng)RhoA的表達(dá)可以抑制神經(jīng)元軸突的生長(zhǎng)。同時(shí)有研究顯示,Nogo-66可能具有NgR識(shí)別域和NgR結(jié)合域,來(lái)自Nogo-66序列的小分子可以競(jìng)爭(zhēng)性結(jié)合NgR,從而阻止Nogo-66與NgR的結(jié)合,克服髓鞘造成的抑制。Nogo是髓鞘抑制分子中被研究得較早和較為深入的一個(gè),具有一定的代表性,但是,對(duì)于Nogo-66與NgR識(shí)別和激活的具體位點(diǎn)目前還沒有報(bào)道。如果能夠同時(shí)從Nogo-66和NgR兩方面著手,阻止二者的識(shí)別,那么來(lái)自Nogo-66的抑制信號(hào)將從此中斷,不再向下傳遞,使中樞神經(jīng)元不會(huì)受到Nogo-66的影響,為再生創(chuàng)造有利的微環(huán)境。 在本研究中,根據(jù)Nogo-66中NgR結(jié)合關(guān)鍵序列合成了兩條含有10個(gè)氨基酸殘基的小肽,肽II和肽III,并運(yùn)用神經(jīng)元原代培養(yǎng)、免疫組織(細(xì)胞)化學(xué)、RT-PCR等方法,研究了肽II和肽III對(duì)小腦顆粒細(xì)胞(cerebellum granule cell,CGC)突起生
[Abstract]:The adult mammalian central nervous system (central nervous system, CNS) is difficult to regenerate after injury, and the result is the permanent loss of certain functions. The peripheral nervous system (peripheral nervous system, PNS) can be regenerated after damage and can be well recovered in function. However, a significant regeneration phenomenon can be observed in transplantation of embryonic peripheral nerve tissue at the damaged CNS site. This indicates that CNS is not lack of regenerative ability, but there is an unfavorable factor for regeneration in the local microenvironment after injury. It is known that there are many kinds of neurite regeneration inhibitory molecules in CNS myelin sheath, such as Nogo, myelin associated glycoprotein (MAG), oligodendrocyte associated glycoprotein (oligodendrocyte myelin associated glycoprotein, OMgp). In order to overcome the effect of myelin inhibitor, researchers have tried many different methods, such as anti Nogo-A antibody IN-1, knockout Nogo gene and Nogo molecule antagonist, but have not achieved very satisfactory results. In recent years, there are three subtypes of Nogo, namely Nogo-A, B and C. Their C- ends are highly homologous, including two transmembrane domains and a short extracellular ring structure (Nogo-66). The subtype of inhibition in CNS is Nogo-A. According to its function, it can be divided into two parts: amino-Nogo and Nogo-66. Interestingly, though OMgp, MAG and Nogo-A have no similarity in sequences, they can transmit signals through the same receptor NgR, which may be the result of their similarity in spatial structure. NgR has no intracellular structure and can only transmit signals through a co receptor. RhoA is an important molecule in this information transduction pathway. Directly or indirectly enhancing the expression of RhoA can inhibit the growth of neuronal axons. Meanwhile, studies have shown that Nogo-66 may have NgR recognition domain and NgR binding domain, and small molecules from Nogo-66 sequences can compete with NgR to prevent Nogo-66 from binding to NgR and overcome myelin inhibition. Nogo is a relatively early and in-depth study of myelin inhibitory molecules. It has a certain representativeness. However, the specific loci for recognition and activation of Nogo-66 and NgR have not been reported yet. If we can start from the two aspects of Nogo-66 and NgR and prevent the identification of the two, then the inhibitory signals from Nogo-66 will be interrupted from this point, and no longer transmit down, so that the central neurons will not be affected by Nogo-66 and create favorable microenvironment for regeneration.
【學(xué)位授予單位】：第三軍醫(yī)大學(xué)
【學(xué)位級(jí)別】：博士
【學(xué)位授予年份】：2006
【分類號(hào)】：R341

【引證文獻(xiàn)】

相關(guān)碩士學(xué)位論文 前1條

1 崔乃松;針康法對(duì)腦缺血大鼠運(yùn)動(dòng)功能及缺血區(qū)皮質(zhì)Nogo-A表達(dá)的影響[D];黑龍江中醫(yī)藥大學(xué);2013年

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