張?jiān)汽? 王 林, 劉鐵民

(聊城大學(xué)體育學(xué)院, 聊城 252059)

·綜 述·

PI3K/Akt和AMPK信號通路在運(yùn)動(dòng)誘導(dǎo)的嚙齒動(dòng)物骨骼肌內(nèi)GLUT4轉(zhuǎn)位和表達(dá)中的作用

張?jiān)汽? 王 林, 劉鐵民

(聊城大學(xué)體育學(xué)院, 聊城 252059)

骨骼肌在葡萄糖穩(wěn)態(tài)中扮演重要作用，葡萄糖轉(zhuǎn)運(yùn)體4(glucose transporter 4，GLUT4)作為骨骼肌內(nèi)最主要的葡萄糖轉(zhuǎn)運(yùn)蛋白，其轉(zhuǎn)位和表達(dá)的變化與胰島素抵抗的發(fā)生密切相關(guān)。本文綜述了近年來關(guān)于嚙齒動(dòng)物骨骼肌內(nèi)GLUT4轉(zhuǎn)位和表達(dá)的運(yùn)動(dòng)激活以及磷脂酰肌醇-3-激酶(phosphatidylinositol 3-kinases，PI3K)/蛋白激酶B(protein kinase B，Akt)和腺苷酸活化蛋白激酶(AMP-activated protein kinase，AMPK)信號通路介導(dǎo)運(yùn)動(dòng)改善骨骼肌葡萄糖攝取的研究進(jìn)展，旨在為全面了解和明確運(yùn)動(dòng)影響嚙齒動(dòng)物骨骼肌內(nèi)GLUT4轉(zhuǎn)位和表達(dá)的機(jī)制。

骨骼肌; 運(yùn)動(dòng); 胰島素抵抗; 葡萄糖轉(zhuǎn)運(yùn)體4(GLUT4); 磷脂酰肌醇-3-激酶(PI3K);蛋白激酶B(Akt); 腺苷酸活化蛋白激酶(AMPK)

骨骼肌是代謝葡萄糖的重要外周組織，其葡萄糖代謝水平在調(diào)節(jié)全身血糖穩(wěn)態(tài)中發(fā)揮著重要作用。葡萄糖轉(zhuǎn)運(yùn)體4(glucose transporter 4，GLUT4)是骨骼肌內(nèi)最重要的葡萄糖轉(zhuǎn)運(yùn)蛋白，其介導(dǎo)的葡萄糖跨細(xì)胞膜的轉(zhuǎn)運(yùn)是骨骼肌葡萄糖代謝的主要限速步驟，而GLUT4的轉(zhuǎn)位和表達(dá)的變化可以在一定程度上反映骨骼肌細(xì)胞的糖代謝狀況。關(guān)于GLUT4的轉(zhuǎn)位存在兩種不同刺激機(jī)制的假說, 胰島素刺激的GLUT4的轉(zhuǎn)位主要涉及磷脂酰肌醇-3-激酶(phosphatidylinositol 3-kinases，PI3K)/蛋白激酶B(protein kinase，Akt)(PI3K/Akt)信號通路, 而運(yùn)動(dòng)刺激的GLUT4的轉(zhuǎn)位主要涉及腺苷酸活化蛋白激酶(AMP-activated protein kinase, AMPK)信號通路[1,2]。

本文基于PI3K/Akt和AMPK信號通路存在復(fù)雜的交互作用以及運(yùn)動(dòng)對這兩種信號通路均可以發(fā)揮影響的理論作為依據(jù)，對運(yùn)動(dòng)刺激的嚙齒動(dòng)物骨骼肌內(nèi)GLUT4轉(zhuǎn)位和表達(dá)中PI3K/Akt和AMPK信號通路的作用進(jìn)行探討，這對于了解胰島素抵抗相關(guān)疾病及評價(jià)運(yùn)動(dòng)對胰島素抵抗相關(guān)疾病的干預(yù)效果具有重要意義。

1 PI3K/Akt和AMPK信號通路與嚙齒動(dòng)物骨骼肌內(nèi)GLUT4轉(zhuǎn)位和表達(dá)

1.1 骨骼肌內(nèi)GLUT4的轉(zhuǎn)位和表達(dá)

GLUT4為跨膜轉(zhuǎn)運(yùn)糖蛋白，相對分子質(zhì)量約為45 000～55 000，由12個(gè)跨膜片段(M1～M12)和1個(gè)位于N 端的胞外環(huán)狀結(jié)構(gòu)域組成。由GLUT4介導(dǎo)的葡萄糖攝取是骨骼肌利用葡萄糖的主要限速步驟，GLUT4的表達(dá)減少、轉(zhuǎn)位受阻及含GLUT4的囊泡不能與細(xì)胞膜融合或已融合但GLUT4活性降低等因素被認(rèn)為是導(dǎo)致骨骼肌葡萄糖攝取缺陷，最終引起胰島素抵抗的主要因素[3,4]。有研究表明[5]，GLUT4基因敲除小鼠出現(xiàn)胰島素抵抗和葡萄糖耐受不良，靶向破壞肌肉的GLUT4, 引起GLUT4的蛋白表達(dá)減少，會(huì)使參與轉(zhuǎn)位的GLUT4的數(shù)量減少，導(dǎo)致骨骼肌細(xì)胞對葡萄糖的攝取與利用發(fā)生障礙，進(jìn)而減弱胰島素信號轉(zhuǎn)導(dǎo)，并最終引起胰島素抵抗的發(fā)生。

骨骼肌細(xì)胞有一個(gè)復(fù)雜的膜系統(tǒng)，其中包括表面細(xì)胞膜和起源于橫小管的膜內(nèi)陷(T-小管)。基礎(chǔ)狀態(tài)下，由于缺乏刺激，GLUT4主要儲存于細(xì)胞內(nèi)的囊泡，受刺激時(shí)這些囊泡轉(zhuǎn)位至質(zhì)膜系統(tǒng)，囊泡膜與質(zhì)膜發(fā)生融合，GLUT4插入質(zhì)膜以增加葡萄糖攝取[6-9]。對新生SD大鼠的骨骼肌細(xì)胞進(jìn)行原代培養(yǎng)，結(jié)果表明胰島素和運(yùn)動(dòng)刺激通過不同的信號途徑促進(jìn)骨骼肌細(xì)胞GLUT4轉(zhuǎn)位至質(zhì)膜[10]。

1.2 PI3K/Akt信號通路與骨骼肌內(nèi)GLUT4轉(zhuǎn)位和表達(dá)

胰島素刺激的骨骼肌內(nèi)GLUT4的轉(zhuǎn)位主要涉及PI3K/Akt信號通路。主要步驟如下: 胰島素與胰島素受體結(jié)合，繼而激活胰島素受體底物(insulin receptor substrate, IRS)和PI3K, 導(dǎo)致磷脂酰肌醇三磷酸(phosphatidylinositol 3-phosphate，PIP3)的產(chǎn)生;隨后PIP3分別與Akt和非典型蛋白激酶 C(atypical protein kinase C，aPKC)結(jié)合, 進(jìn)而促使GLUT4轉(zhuǎn)位至表面細(xì)胞膜以攝取葡萄糖[1]。雖然IRS與PI3K的結(jié)合對于高脂飲食誘導(dǎo)的胰島素抵抗的SD大鼠骨骼肌內(nèi)GLUT4的轉(zhuǎn)位是必要的, 但是二者的結(jié)合還不足以刺激GLUT4介導(dǎo)的葡萄糖攝取的增加, 葡萄糖攝取的增加需要Akt的參與[11]。Akt是一種絲氨酸-蘇氨酸蛋白激酶, PIP3與Akt的PH結(jié)構(gòu)域結(jié)合, 促進(jìn)Akt激活, 進(jìn)而促進(jìn)GLUT4的轉(zhuǎn)位和肌肉葡萄糖攝取[12]。有研究表明[9], Akt的激活可以促進(jìn)骨骼肌內(nèi)GLUT4的轉(zhuǎn)位, 從而增加肌細(xì)胞的葡萄糖攝取。在胰島素刺激下, GLUT4從細(xì)胞內(nèi)囊泡向質(zhì)膜的轉(zhuǎn)位可以促進(jìn)葡萄糖攝取增加大約40%[13]。與Akt對GLUT4轉(zhuǎn)位的作用類似, 最近一些證據(jù)表明[14], aPKC ζ/λ在胰島素刺激的骨骼肌GLUT4轉(zhuǎn)位和葡萄糖攝取中也起著重要作用, aPKC ζ/λ的磷酸化激活可以促進(jìn)胰島素刺激的GLUT4的轉(zhuǎn)位和L6肌管對葡萄糖的攝取 。PIP3與aPKC ζ/λ的調(diào)節(jié)域結(jié)合導(dǎo)致aPKC ζ/λ的激活, 進(jìn)而促進(jìn)GLUT4的轉(zhuǎn)位[15]。

雖然通過Akt刺激骨骼肌內(nèi)GLUT4轉(zhuǎn)位的精確分子機(jī)制仍然不是很清晰, 但相對分子量為160 000 的Akt底物AS160被認(rèn)為是Akt介導(dǎo)GLUT4轉(zhuǎn)位的一個(gè)重要的調(diào)控分子[16]。AS160是一種可以與Rab蛋白發(fā)生特異性作用的GTP 酶激活蛋白。Rab蛋白是細(xì)胞內(nèi)囊泡運(yùn)輸?shù)姆肿娱_關(guān), 其通過與上游調(diào)控因子以及下游效應(yīng)子的相互作用, 參與了囊泡的形成、轉(zhuǎn)運(yùn)、粘附、錨定和融合等過程。AS160被認(rèn)為通過與Rab蛋白相互作用參與了Akt對GLUT4的轉(zhuǎn)位調(diào)節(jié)[17-20]。當(dāng)AS160的Ser588和Thr642位點(diǎn)突變?yōu)楸彼釙r(shí),可以顯著抑制胰島素刺激的GLUT4轉(zhuǎn)位[17], 顯示AS160在胰島素刺激的GLUT4的轉(zhuǎn)位中發(fā)揮著重要作用。但也有研究表明[21], Akt促進(jìn)GLUT4轉(zhuǎn)位過程的調(diào)節(jié)是非AS160依賴的, 并且已證明其他參與GLUT4轉(zhuǎn)位的Akt底物, 如含F(xiàn)YVE指磷酸肌醇激酶(FYVE finger-containing phosphoinositide kinase, PIKfyve)[22]。Roach等[23]研究表明, 與AS160關(guān)系密切的TBC1域家族成員1(TBC1 domain family member 1, TBCID1)也有類似的可以被Akt磷酸化的位點(diǎn)?？梢夾kt促進(jìn)GLUT4轉(zhuǎn)位過程中AS160的作用仍然撲朔迷離, 很有可能AS160和其他Akt底物一起共同參與了GLUT4的轉(zhuǎn)位過程。

1.3 AMPK信號通路與骨骼肌內(nèi)GLUT4轉(zhuǎn)位和表達(dá)

除PI3K/Akt信號通路，AMPK的激活也可以促進(jìn)GLUT4的轉(zhuǎn)位和表達(dá)。5-氨基咪唑-4-甲酰胺核苷酸(5-Aminoimidazole-4-carboxamide 1-β-D-ribofuranoside, AICAR)(AMPK激活劑)激活A(yù)MPK后可以上調(diào)大鼠比目魚肌細(xì)胞以及原代培養(yǎng)的肌細(xì)胞的葡萄糖攝取和GLUT4 mRNA的表達(dá), 提示GLUT4是AMPK 參與糖代謝調(diào)節(jié)的重要下游靶點(diǎn)[24,25]。Hommes等[26]研究表明，給大鼠注射AICAR引起AMPK的激活，引起大鼠腓腸肌內(nèi)GLUT4的蛋白表達(dá)增加。李蕾等[27]研究表明, AMPK可以通過調(diào)節(jié)糖代謝的下游靶蛋白, 增加GLUT4的轉(zhuǎn)位, 進(jìn)而增強(qiáng)肌肉胰島素敏感性。有研究報(bào)道[1], 在AMPK活化的過程中同樣會(huì)激活A(yù)S160。因此，AS160可能是調(diào)節(jié)骨骼肌內(nèi)GLUT4轉(zhuǎn)位的PI3K/Akt和AMPK信號通路的一個(gè)關(guān)鍵交匯點(diǎn)。但胰島素刺激和AMPK激活對AS160的影響似乎是通過兩個(gè)不同的通路。渥曼青霉素(PI3K抑制劑)可以抑制胰島素對離體大鼠骨骼肌AS160的磷酸化效果，但AICAR所致AMPK激活和AS160磷酸化增加并不涉及Akt的磷酸化改變[28]。

2 PI3K/Akt和AMPK信號通路在運(yùn)動(dòng)影響嚙齒動(dòng)物骨骼肌內(nèi)GLUT4轉(zhuǎn)位和表達(dá)中的作用

2.1 PI3K/Akt和AMPK信號通路存在復(fù)雜的交互作用

PI3K/Akt和AMPK信號通路并不是彼此孤立，而是存在復(fù)雜的交互作用。首先，AMPK對PI3K/ Akt信號通路可以發(fā)揮雙向調(diào)節(jié)作用。有研究者認(rèn)為[28-31]，AMPK的激活以及AICAR的使用可以促進(jìn)IRS、PI3K和Akt等多種PI3K/Akt信號通路分子的活性增加。通過AICAR激活小鼠C2C12肌管的AMPK, 結(jié)果表明AMPK的激活與IRS-1的Ser789位點(diǎn)的磷酸化之間存在直接的相互作用[30]。Jakobsen等[32]研究表明，AMPK的激活可以引起小鼠C2C12肌管的IRS-1的Ser789位點(diǎn)的磷酸化水平增加，進(jìn)而引起PI3K的活性增加。但Tzatsos等[33]報(bào)道，AMPK的激活可以促進(jìn)IRS-1的Ser794位點(diǎn)磷酸化，進(jìn)而抑制PI3K/Akt信號通路。而IRS-1的Ser794位點(diǎn)磷酸化增加對PI3K/Akt信號通路的抑制可以導(dǎo)致GLUT4的轉(zhuǎn)位減少[34-36]。其次, PI3K/Akt信號通路可以調(diào)節(jié)AMPK的活性，比如Akt的激活可以下調(diào)AMPK的活性[37,38]。Rider等[39]認(rèn)為，Akt所致的AMPK的Ser487或Ser491位點(diǎn)的磷酸化是胰島素引起AMPK活性下降的關(guān)鍵步驟。

Liu等[40]研究表明，高脂喂養(yǎng)引起大鼠骨骼肌內(nèi)AMPKα的表達(dá)和活性受損，而二甲雙胍激活A(yù)MPK后可以明顯改善高脂飲食誘導(dǎo)的胰島素抵抗，提示AMPK的活化與胰島素信號通路之間存在關(guān)聯(lián)，而AMPK活性的下降可能會(huì)加速胰島素抵抗和代謝異常的進(jìn)展。Jessen等[41]報(bào)道，運(yùn)動(dòng)激活A(yù)MPK后，可以通過刺激GLUT4的表達(dá)調(diào)節(jié)Wistar大鼠骨骼肌的胰島素敏感性。那么在運(yùn)動(dòng)影響骨骼肌GLUT4的轉(zhuǎn)位和表達(dá)中PI3K/Akt和AMPK信號通路是否共同發(fā)揮了作用呢？

2.2 PI3K/Akt信號通路在運(yùn)動(dòng)影響骨骼肌內(nèi)GLUT4轉(zhuǎn)位和表達(dá)中的作用

對骨骼肌胰島素抵抗的研究中, PI3K/Akt信號通路受到眾多研究者的關(guān)注，但Krook等[42]認(rèn)為運(yùn)動(dòng)對骨骼肌內(nèi)GLUT4轉(zhuǎn)位和表達(dá)的影響與PI3K/Akt信號通路無關(guān)。對肥胖Zucker大鼠的研究表明，運(yùn)動(dòng)可以上調(diào)GLUT4的蛋白表達(dá)，但I(xiàn)RS-1的酪氨酸磷酸化水平并無明顯變化[43]。這些研究似乎暗示PI3K/Akt信號通路在運(yùn)動(dòng)調(diào)節(jié)骨骼肌內(nèi)GLUT4的轉(zhuǎn)位和表達(dá)中并不起作用。然而，有研究者持不同意見，Chibalin等[44]的研究表明，游泳運(yùn)動(dòng)可增強(qiáng)Wistar大鼠IRS-2、PI3K和Akt的活性，同時(shí)增加GLUT4的蛋白表達(dá)。研究結(jié)果的不一致可能與采用的動(dòng)物模型、使用的干預(yù)手段及檢測的信號分子等不同有關(guān)。

2.3 AMPK信號通路在運(yùn)動(dòng)影響骨骼肌內(nèi)GLUT4轉(zhuǎn)位和表達(dá)中的作用

AMPK信號通路在運(yùn)動(dòng)增加GLUT4轉(zhuǎn)位和表達(dá)中發(fā)揮重要作用。一方面, 運(yùn)動(dòng)可以誘導(dǎo)GLUT4的轉(zhuǎn)位，其機(jī)制涉及AMPK信號通路[45]。另一方面，運(yùn)動(dòng)可以通過激活A(yù)MPK信號通路增加骨骼肌GLUT4 mRNA和蛋白表達(dá)[46]。有研究者認(rèn)為[42], AMPK是通過非胰島素依賴的機(jī)制增加骨骼肌葡萄糖攝取, 并有一些研究者對此機(jī)制進(jìn)行了深入探討。有研究者報(bào)道[47], AMPK可以通過直接磷酸化過氧化物酶體增殖活化受體γ輔助活化因子1α(α subunit of peroxisome proliferators-activated receptor-γ coactivator-1, PGC-1α)調(diào)節(jié)骨骼肌GLUT4的表達(dá)。還有研究者認(rèn)為[48,49], AMPK可以通過對p38分裂原激活的蛋白激酶(p38 mitogen activated protein kinases, p38MAPK)或內(nèi)皮型一氧化氮合酶(endothelial nitric oxide synthase，eNOS)的作用刺激GLUT4轉(zhuǎn)位。此外，AMPK的主要上游激酶(liver kinase B1, LKB1)可能也參與了骨骼肌葡萄糖攝取。據(jù)報(bào)道[50], 骨骼肌缺乏LKB1導(dǎo)致肌肉收縮誘導(dǎo)的葡萄糖攝取受到抑制。值得關(guān)注的是, 抑制AMPK活性對肌肉收縮誘導(dǎo)的小鼠骨骼肌葡萄糖攝取并無明顯影響[51,52]?？紤]到這些研究結(jié)果存在的差異，有必要進(jìn)一步審查AMPK信號通路在運(yùn)動(dòng)影響骨骼肌內(nèi)GLUT4轉(zhuǎn)運(yùn)和表達(dá)中的作用。

2.4 PI3K/Akt和AMPK信號通路可能共調(diào)運(yùn)動(dòng)對骨骼肌內(nèi)GLUT4轉(zhuǎn)位和表達(dá)的影響

早期的研究表明, 胰島素和運(yùn)動(dòng)通過不同的信號傳導(dǎo)機(jī)制促進(jìn)GLUT4轉(zhuǎn)位和葡萄糖攝取。然而對PI3K下游的胰島素信號分子的進(jìn)一步研究表明, aPKC ζ/λ在胰島素和運(yùn)動(dòng)刺激小鼠肌肉內(nèi)GLUT4轉(zhuǎn)位和葡萄糖攝取中均發(fā)揮了作用[53,54]。Lessard 等[55]研究表明，運(yùn)動(dòng)訓(xùn)練可以增加高脂喂養(yǎng)大鼠骨骼肌AMPKα活性，同時(shí)可通過增強(qiáng)胰島素信號通路，促進(jìn)葡萄糖攝取。這些研究提示PI3K/Akt和AMPK信號通路可能共調(diào)運(yùn)動(dòng)對骨骼肌內(nèi)GLUT4轉(zhuǎn)位和表達(dá)的影響。

有研究者報(bào)道，在某些情況下Akt的激活與PI3K之間存在不一致[55]，原因可能與Akt存在非PI3K依賴途徑調(diào)節(jié)有關(guān)，如鈣/鈣調(diào)素依賴性蛋白激酶(calcium-calmodulin dependent protein kinase，CaMK)的活化可直接磷酸化Akt的Thr308位點(diǎn)[56]。值得注意的是，CaMK 除了可調(diào)節(jié)Akt的活性外，還可影響AMPK的激活。李良剛等[25]認(rèn)為，AMPK可能位于CaMK途徑的下游來調(diào)節(jié)骨骼肌細(xì)胞GLUT4 mRNA的表達(dá)?？梢?，AMPK信號通路與胰島素信號通路在調(diào)節(jié)運(yùn)動(dòng)引起的骨骼肌內(nèi)GLUT4轉(zhuǎn)位和表達(dá)方面存在密切的聯(lián)系，CaMK可能參與了這種聯(lián)系。

很多研究者[57-59]認(rèn)為AMPKα的Thr172位點(diǎn)磷酸化是其激活的關(guān)鍵步驟。但有研究表明[60], AMPKα的Ser485位點(diǎn)的磷酸化也參與了AMPK活性的調(diào)節(jié)。值得關(guān)注的是，AMPKα的 Ser485位點(diǎn)是一個(gè)自我磷酸化位點(diǎn)，并且此位點(diǎn)是Akt的一個(gè)靶點(diǎn)，即Akt可以通過磷酸化AMPK的Ser485位點(diǎn)調(diào)節(jié)AMPK的活性。那么，Akt對AMPK的Ser485位點(diǎn)的調(diào)節(jié)作用是否參與了運(yùn)動(dòng)對GLUT4的轉(zhuǎn)位和表達(dá)的影響呢？這些問題均有待于進(jìn)一步的研究給予證實(shí)。除AMPK信號通路，運(yùn)動(dòng)時(shí)還存在其它機(jī)制參與了對骨骼肌葡萄糖攝取的調(diào)節(jié)。有研究顯示[61]，AMPK失活的轉(zhuǎn)基因小鼠在缺氧或AICAR激活后己糖攝取能力被完全阻斷，但收縮刺激的己糖攝取只是部分地被抑制。因此，運(yùn)動(dòng)刺激的骨骼肌內(nèi)GLUT4轉(zhuǎn)位和表達(dá)增加很可能是多條信號通路共同作用的結(jié)果，而非PI3K依賴的Akt信號通路很可能參與其中。

3 小結(jié)

由于PI3K/Akt和AMPK信號通路之間存在復(fù)雜的交互作用，并且二者均與骨骼肌內(nèi)GLUT4的轉(zhuǎn)位和表達(dá)有關(guān)，因此本文對近年來關(guān)于GLUT4的轉(zhuǎn)位和表達(dá)的運(yùn)動(dòng)激活以及PI3K/ Akt和AMPK信號通路介導(dǎo)運(yùn)動(dòng)改善嚙齒動(dòng)物骨骼肌葡萄糖攝取的研究進(jìn)展進(jìn)行了綜述，但是運(yùn)動(dòng)能否通過PI3K/Akt或非PI3K依賴性Akt信號通路以及AMPK信號通路共調(diào)運(yùn)動(dòng)刺激的GLUT4的轉(zhuǎn)位和表達(dá)仍然存在諸多的不確定性，對于可能聯(lián)系這種共調(diào)作用的具體分子機(jī)制依然不甚明了。所以進(jìn)一步明確運(yùn)動(dòng)刺激下參與GLUT4轉(zhuǎn)位和表達(dá)的多種信號通路的作用，尤其是深究運(yùn)動(dòng)調(diào)控的GLUT4改變是否涉及AMPK和PI3K/Akt信號通路之間的交互作用是有必要的，在這方面的研究進(jìn)展將有助于胰島素抵抗相關(guān)慢性疾病的防治。

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PI3K/Akt and AMPK Signaling Pathway and Effect of Exercise on Rodent Skeletal Muscle GLUT4 Translocation and Expression

ZHANG Yun-li, WANG Lin, LIU Tie-min
(Liaocheng University, Liaocheng 252059, China)

Skeletal muscles play an important role in glucose homeostasis. The translocation and expression changes of glucose transporter 4 (GLUT4) as one of the most important glucose transporter proteins in skeletal muscle are closely associated with insulin resistance. This paper reviewed the recent research progress on the exercise-induced translocation and expression of GLUT4 as well as the improvement of exercise-induced glucose uptake by phosphatidylinositol 3-kinases (PI3K) / protein kinase B (Akt) and AMP-activated protein kinase (AMPK) signaling pathways in rodent skeletal muscle. The purpose of this paper is to clearly understand the mechanism underlying GLUT4 translocation and expression in rodent skeletal muscles.

Skeletal muscle; Exercise; Insulin resistance; Glucose transporter 4 (GLUT4); Phosphatidylinositol 3-kinases (PI3K); Protein kinase B (Akt); AMP-activated protein kinase (AMPK)

Q95-33

A

1674-5817(2017)01-0076-07

10.3969/j.issn.1674-5817.2017.01.017

2016-06-15

山東省自然科學(xué)基金資助項(xiàng)目(ZR2011CM040)

張?jiān)汽?1977-), 女, 講師,

E-mail: zhangyunli@lcu.edu.cn