本文選題：NMDA受體　切入點(diǎn)：conantokins　出處：《中國人民解放軍軍事醫(yī)學(xué)科學(xué)院》2010年碩士論文　論文類型：學(xué)位論文

【摘要】： Conantokins (Con-)是芋螺活性肽的一個(gè)重要家族,能特異性作用于N-甲基-天門冬氨酸受體(NMDAR)及其亞型,是目前發(fā)現(xiàn)的該受體的唯一一類多肽抑制劑。NMDA受體NR2B亞基與鎮(zhèn)痛、神經(jīng)保護(hù)、戒毒等密切相關(guān),NR2B亞基特異抑制劑對研發(fā)低副作用的鎮(zhèn)痛、神經(jīng)保護(hù)、戒毒藥具有誘人前景。 前期本實(shí)驗(yàn)室發(fā)現(xiàn)con-G及其突變體對嗎啡依賴小鼠的催促戒斷跳躍具有顯著抑制作用,且抑制活性與其對NR2B亞基的選擇性密切相關(guān),但該類抑制劑對小鼠嗎啡精神依賴沒有研究。本論文在前期工作基礎(chǔ)上,開展了對NMDA受體NR2B亞基選擇性抑制劑Conantokins的進(jìn)一步篩選并初步研究了其抑制嗎啡身體依賴發(fā)展、精神依賴發(fā)展、表達(dá)的新功能的作用機(jī)理,獲得了如下新結(jié)果： (1)篩選了21個(gè)conantokins天然肽及其突變體,找到了一種副作用低且特異性作用于NMDA受體NR2B亞基的抑制劑con-T-[M8Q],不僅能有效抑制小鼠的嗎啡身體依賴的表達(dá)與發(fā)展,而且不影響小鼠的運(yùn)動(dòng)功能及自發(fā)活動(dòng)。 (2) Con-T-[M8Q]對小鼠的嗎啡精神依賴的表達(dá)與發(fā)展具有顯著抑制作用,5nmol/kg的劑量con-T[M8Q]幾乎能完全抑制小鼠嗎啡精神依賴的表達(dá)及發(fā)展。 (3)研究了嗎啡依賴小鼠在給不同劑量con-T-[M8Q]抑制劑后主要相關(guān)信號(hào)通路的變化,結(jié)果表明：Con-T[M8Q]能夠抑制嗎啡依賴小鼠NMDA受體NR2B亞基1472位酪氨酸的磷酸化水平,下調(diào)非磷酸化NR2B亞基的表達(dá)水平；除CaMKI mRNA的表達(dá)量和抑制劑劑量之間沒有明顯規(guī)律性變化外,CaMKIIa、β單體及CaMKIV mRNA的表達(dá)量均隨抑制劑劑量的增高而降低；Con-T[M8Q]同時(shí)還下調(diào)ERK、c-fos蛋白的表達(dá)水平。 該工作為嗎啡依賴相關(guān)機(jī)理研究提供了一個(gè)很好的研究工具,并為相關(guān)抑制劑的應(yīng)用提供了機(jī)理支持。
[Abstract]:Conantokins Con-Con-is an important family of conoc active peptides, which can act specifically on N-methyl-aspartate receptor (NMDAR) and its subtypes. It is the only type of polypeptide inhibitor. NMDA receptor NR2B subunit and analgesia, neuroprotection. Detoxification and other closely related NR2B subunit specific inhibitors have attractive prospects for the development of analgesic, neuroprotective and abstinent poisons with low side effects. It was found in our laboratory that con-G and its mutants had a significant inhibitory effect on withdrawal jumping in morphine dependent mice, and the inhibitory activity was closely related to their selectivity to NR2B subunits. On the basis of previous work, this thesis has carried out further screening of Conantokins, a selective inhibitor of NMDA receptor NR2B subunit, and studied its inhibition on the development of morphine physical dependence. The mechanism of the new function of spiritual dependence development and expression has obtained the following new results:. We screened 21 conantokins natural peptides and their mutants, and found an inhibitor con-T- [M8Q], which has low side effect and specific effect on NR2B subunit of NMDA receptor, which can not only effectively inhibit the expression and development of morphine physical dependence in mice. Moreover, the motor function and spontaneous activity of mice were not affected. (2) Con-T- [M8Q] had a significant inhibitory effect on the expression and development of morphine dependence in mice. Con-T (5 nmol / kg) [M8Q] could almost completely inhibit the expression and development of morphine dependence in mice. The changes of the main related signaling pathways in morphine dependent mice after different doses of con-T- [M8Q] inhibitor were studied. The results showed that: Con-T [M8Q] could inhibit tyrosine phosphorylation of NMDA receptor NR2B subunit 1472 in morphine dependent mice. The expression of non-phosphorylated NR2B subunits was down-regulated. The expression of CaMKIIa, 尾 monomer and CaMKIV mRNA decreased with the increase of inhibitor dose, and decreased the expression level of ERK c-fos protein with the increase of inhibitor dose. This work provides a good tool for the study of morphine dependence mechanism and provides mechanism support for the application of related inhibitors.
【學(xué)位授予單位】：中國人民解放軍軍事醫(yī)學(xué)科學(xué)院
【學(xué)位級別】：碩士
【學(xué)位授予年份】：2010
【分類號(hào)】：R341

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本文編號(hào)：1646342