鋅指蛋白ZBTB20通過調(diào)節(jié)傷害感受神經(jīng)元TRP通道調(diào)控傷害感受和痛覺
發(fā)布時(shí)間：2018-07-15 12:16
【摘要】：疼痛的調(diào)控機(jī)制一直是神經(jīng)生物學(xué)的研究熱點(diǎn)。在哺乳動(dòng)物中,背根神經(jīng)節(jié)(dorsal root ganglion, DRG)的小神經(jīng)元是感受和傳導(dǎo)疼痛信號(hào)的傷害感受神經(jīng)元。傷害感受小神經(jīng)元又可進(jìn)一步分成肽能和非肽能兩個(gè)不同的亞群。肽能小神經(jīng)元可分泌神經(jīng)肽、P物質(zhì)、降鈣素基因相關(guān)肽(calcitonin-gene related peptide, CGRP),表達(dá)神經(jīng)生長(zhǎng)因子受體TrkA。非肽能小神經(jīng)元表達(dá)神經(jīng)營(yíng)養(yǎng)因子受體c-Ret,受膠質(zhì)細(xì)胞源性神經(jīng)營(yíng)養(yǎng)因子(glial-derived neurotrophic factor, GDNF)等的調(diào)節(jié),表達(dá)G蛋白偶聯(lián)受體家族Mrgpr和嘌呤受體P2X3,植物凝集素(isolectin B4, IB4)標(biāo)記陽性。痛覺感受是通過DRG中傷害感受神經(jīng)元上的通道或受體感受傷害性刺激的,瞬時(shí)感受器電位(transient receptor potential,TRP)通道在其中起著重要的作用。TRP通道是溫度感受相關(guān)的非選擇性陽離子通道,激活時(shí)主要引起Ca2+內(nèi)流,包括6個(gè)亞家族：TRPC、TRPV、TRPM、TRPML、TRPPP和TRPA。其中TRPV1是感受傷害性熱刺激的內(nèi)源性感受器,TRPA1與TRPM8則在感受傷害性冷刺激中發(fā)揮重要作用。但是這些通道的表達(dá)如何調(diào)節(jié)目前還知之甚少。許多轉(zhuǎn)錄因子在傷害感受神經(jīng)元的發(fā)育過程中發(fā)揮了重要的調(diào)節(jié)作用。其中,神經(jīng)發(fā)生素1(neurogenin 1,NGN1)是大部分傷害感受神經(jīng)元發(fā)育所必需的。同源基因Brn3a和鋅指蛋白klf7在傷害感受神經(jīng)元存活及維持TrkA表達(dá)等方面具有重要的作用。Runxl(Runt domain transcription factor 1)可激活多種與痛覺相關(guān)的通道蛋白及受體,如TRPV1、TRPA1、μ型阿片樣受體(μ opioid receptor, MOR)和嘌呤能受體P2X3等,并抑帶CGRP和P物質(zhì)的表達(dá)。此外,轉(zhuǎn)錄因子Tlx3能與Runxl共同協(xié)調(diào)調(diào)節(jié)一些傷害感受神經(jīng)元及嘌呤受體的表達(dá)。然而,目前在調(diào)節(jié)傷害感受神經(jīng)元TRP通道表達(dá)的轉(zhuǎn)錄因子研究方面還未見報(bào)道。鋅指蛋白ZBTB20是導(dǎo)師章衛(wèi)平所在課題組自主發(fā)現(xiàn)并率先報(bào)道的新型轉(zhuǎn)錄因子。ZBTB20由741個(gè)氨基酸殘基組成,N端含有BTB/POZ結(jié)構(gòu)域,C端含有5個(gè)C2H2鋅指結(jié)構(gòu)域,是BTB鋅指蛋白亞家族成員之一。研究發(fā)現(xiàn)ZBTB20在中樞神經(jīng)系統(tǒng)中高表達(dá),并且在海馬的分化發(fā)育及功能方面具有重要的作用,但是它對(duì)周圍神經(jīng)系統(tǒng)的作用還未見報(bào)道。在本研究中我們發(fā)現(xiàn)ZBTB20在DRG中傷害感受神經(jīng)元高表達(dá)。通過建立外周傷害感受神經(jīng)元特異性ZBTB20敲除(peripheral nociceptor-specific ZBTB20 knockout, PN-ZB20KO)小鼠模型并結(jié)合組織學(xué)、行為學(xué)、電生理及分子生物學(xué)等研究手段,我們發(fā)現(xiàn)PN-ZB20KO小鼠DRG中TRP通道家族TRPV1、TRPA1和TRPM8表達(dá)顯著降低,而且這些通道激動(dòng)劑誘發(fā)的鈣內(nèi)流以及通道電流下降。PN-ZB20KO小鼠對(duì)熱刺激、機(jī)械刺激和免疫刺激引起的疼痛反應(yīng)減弱。我們的研究表明ZBTB20通過調(diào)節(jié)傷害感受神經(jīng)元TRP通道的表達(dá)調(diào)控傷害感受和痛覺。
[Abstract]:The mechanism of pain regulation has been a hot topic in neurobiology. In mammals, the small neurons of the dorsal root ganglion (dorsal root ganglion, DRG) are nociceptive neurons that sense and transmit pain signals. The nociceptive small neurons can be further divided into two subgroups of peptidergic and non-peptidergic. Small peptidergic neurons secrete neuropeptide substance P, calcitonin-gene related peptide, and express nerve growth factor receptor TrkA. Non-peptidergic small neurons expressed neurotrophic factor receptor c-Ret, which was regulated by glial-derived neurotrophic factor (GDNF), and expressed isolectin B4 (IB4) labeled isolectin B4 in the G protein-coupled receptor family Mrgpr, P2X3 and isolectin B4 (IB4). Pain perception is induced by nociceptive stimulation through nociceptive neurons or receptors in DRGs, in which transient receptor potential (transient receptor potentialtr) channels play an important role. TRP channels are non-selective cationic channels associated with temperature sensing. During activation, Ca2 + influx was mainly induced, including 6 subfamilies: TRPC, TRPV, TRPMML, TRPPP and TRPA. TRPV1 is the endogenous receptor of nociceptive heat stimulation, and TRPA1 and TRPM8 play an important role in nociceptive cold stimulation. But little is known about how these channels are regulated. Many transcription factors play an important role in the development of nociceptive neurons. Among them, neurogenin 1 NGN1 is necessary for the development of most nociceptive neurons. The homologous genes Brn3a and zinc finger protein klf7 play an important role in the survival of nociceptive neurons and the maintenance of TrkA expression. Runxl (Runt domain transcription factor 1) can activate many channel proteins and receptors associated with pain perception. For example, TRPV1 / TRPA1, 渭 opioid receptor (Mor) and purinergic receptor P2X3, etc., also inhibit the expression of CGRP and substance P. In addition, transcription factor Tlx3 can coordinate with Runxl to regulate the expression of some nociceptive neurons and purine receptors. However, transcriptional factors regulating the expression of TRP channels in nociceptive neurons have not been reported. Zinc finger protein ZBTB20 is a novel transcription factor. ZBTB20 consists of 741 amino acid residues. ZBTB20 contains five C2H2 zinc finger domains at the C-terminal of BTB / POZ domain. It is a member of BTB zinc finger protein subfamily. It has been found that ZBTB20 is highly expressed in the central nervous system and plays an important role in the differentiation and development of the hippocampus, but its effect on the peripheral nervous system has not been reported. In this study, we found that ZBTB 20 is highly expressed in DRG nociceptive neurons. The peripheral nociceptor-specific ZBTB20 knockout (PN-ZB20KO) mouse model was established and combined with histological, behavioral, electrophysiological and molecular biological methods. We found that the expression of TRPV1 / TRPA1 and TRPM8 in DRG of PN-ZB20KO mice was significantly decreased, and the calcium influx induced by these channel agonists and the decrease of channel current in PN-ZB20KO mice were decreased to the pain response induced by thermal, mechanical and immune stimulation. Our study shows that ZBTB20 regulates pain perception and pain perception by regulating the expression of TRP channels in nociceptive neurons.
【學(xué)位授予單位】：第二軍醫(yī)大學(xué)
【學(xué)位級(jí)別】：碩士
【學(xué)位授予年份】：2015
【分類號(hào)】：R402
本文編號(hào)：2124044
[Abstract]:The mechanism of pain regulation has been a hot topic in neurobiology. In mammals, the small neurons of the dorsal root ganglion (dorsal root ganglion, DRG) are nociceptive neurons that sense and transmit pain signals. The nociceptive small neurons can be further divided into two subgroups of peptidergic and non-peptidergic. Small peptidergic neurons secrete neuropeptide substance P, calcitonin-gene related peptide, and express nerve growth factor receptor TrkA. Non-peptidergic small neurons expressed neurotrophic factor receptor c-Ret, which was regulated by glial-derived neurotrophic factor (GDNF), and expressed isolectin B4 (IB4) labeled isolectin B4 in the G protein-coupled receptor family Mrgpr, P2X3 and isolectin B4 (IB4). Pain perception is induced by nociceptive stimulation through nociceptive neurons or receptors in DRGs, in which transient receptor potential (transient receptor potentialtr) channels play an important role. TRP channels are non-selective cationic channels associated with temperature sensing. During activation, Ca2 + influx was mainly induced, including 6 subfamilies: TRPC, TRPV, TRPMML, TRPPP and TRPA. TRPV1 is the endogenous receptor of nociceptive heat stimulation, and TRPA1 and TRPM8 play an important role in nociceptive cold stimulation. But little is known about how these channels are regulated. Many transcription factors play an important role in the development of nociceptive neurons. Among them, neurogenin 1 NGN1 is necessary for the development of most nociceptive neurons. The homologous genes Brn3a and zinc finger protein klf7 play an important role in the survival of nociceptive neurons and the maintenance of TrkA expression. Runxl (Runt domain transcription factor 1) can activate many channel proteins and receptors associated with pain perception. For example, TRPV1 / TRPA1, 渭 opioid receptor (Mor) and purinergic receptor P2X3, etc., also inhibit the expression of CGRP and substance P. In addition, transcription factor Tlx3 can coordinate with Runxl to regulate the expression of some nociceptive neurons and purine receptors. However, transcriptional factors regulating the expression of TRP channels in nociceptive neurons have not been reported. Zinc finger protein ZBTB20 is a novel transcription factor. ZBTB20 consists of 741 amino acid residues. ZBTB20 contains five C2H2 zinc finger domains at the C-terminal of BTB / POZ domain. It is a member of BTB zinc finger protein subfamily. It has been found that ZBTB20 is highly expressed in the central nervous system and plays an important role in the differentiation and development of the hippocampus, but its effect on the peripheral nervous system has not been reported. In this study, we found that ZBTB 20 is highly expressed in DRG nociceptive neurons. The peripheral nociceptor-specific ZBTB20 knockout (PN-ZB20KO) mouse model was established and combined with histological, behavioral, electrophysiological and molecular biological methods. We found that the expression of TRPV1 / TRPA1 and TRPM8 in DRG of PN-ZB20KO mice was significantly decreased, and the calcium influx induced by these channel agonists and the decrease of channel current in PN-ZB20KO mice were decreased to the pain response induced by thermal, mechanical and immune stimulation. Our study shows that ZBTB20 regulates pain perception and pain perception by regulating the expression of TRP channels in nociceptive neurons.
【學(xué)位授予單位】：第二軍醫(yī)大學(xué)
【學(xué)位級(jí)別】：碩士
【學(xué)位授予年份】：2015
【分類號(hào)】：R402
【共引文獻(xiàn)】
相關(guān)博士學(xué)位論文 前2條
1 鄒宇;CGRP和IB4（+）C纖維在神經(jīng)病理性疼痛陽—陰性癥狀中的作用[D];中南大學(xué);2013年
2 汪一;T型鈣通道阻滯劑強(qiáng)化加巴噴丁治療糖尿病神經(jīng)病理性疼痛的效果及可能的機(jī)制[D];北京協(xié)和醫(yī)學(xué)院;2014年
，本文編號(hào)：2124044
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