缺氧時(shí)腦內(nèi)神經(jīng)元保護(hù)性相關(guān)蛋白的調(diào)節(jié)
發(fā)布時(shí)間：2018-09-10 06:59
【摘要】： 缺氧是臨床常見病理現(xiàn)象,可導(dǎo)致多種缺氧性疾病,涉及呼吸、神經(jīng)、心血管等諸多領(lǐng)域。由于腦組織儲(chǔ)能少、耗氧量大,極易產(chǎn)生缺氧性損傷。因此,缺氧時(shí)的腦保護(hù),是神經(jīng)學(xué)研究的重要課題。 腦組織缺氧后,其細(xì)胞內(nèi)ATP生成不足、酸中毒、細(xì)胞膜離子轉(zhuǎn)運(yùn)障礙、膜電位改變等,使神經(jīng)遞質(zhì)合成減少及受體表達(dá)異常,這些功能蛋白的異常,影響了突觸傳遞,導(dǎo)致腦細(xì)胞功能和結(jié)構(gòu)改變。 氨基酸類神經(jīng)遞質(zhì)是腦內(nèi)重要的遞質(zhì)系統(tǒng)。腦細(xì)胞維持正常功能有賴于其中興奮性氨基酸和抑制性氨基酸相互平衡。前者以谷氨酸和天冬氨酸為代表,介導(dǎo)大部分快速興奮性突觸傳遞,后者以γ-氨基丁酸(GABA)和甘氨酸(glycine)為代表,介導(dǎo)大部分快速抑制性突觸傳遞。近來(lái)發(fā)現(xiàn),抑制性氨基酸在保護(hù)腦細(xì)胞、抵抗缺氧/缺血和其它應(yīng)激反應(yīng)中發(fā)揮了重要作用,且抑制性氨基酸對(duì)不同發(fā)育期的神經(jīng)元有不同的作用。然而,在缺氧環(huán)境中,不同年齡神經(jīng)元的GABA受體和glycine受體的表達(dá)情況以及抑制性氨基酸對(duì)這兩個(gè)受體表達(dá)的影響還不很清楚。 腦內(nèi)另一重要的遞質(zhì)系統(tǒng)是乙酰膽堿系統(tǒng),該系統(tǒng)參與了機(jī)體運(yùn)動(dòng)與感覺過(guò)程的信息傳遞。由于膽堿乙酰轉(zhuǎn)移酶(ChAT)是乙酰膽堿合成的限速酶,它的異常與阿爾茨海默病(Alzheimer's disease,AD)等疾病密切相關(guān)。已經(jīng)發(fā)現(xiàn),缺氧影響了乙酰膽堿的代謝,參與了阿爾茨海默病的發(fā)生、發(fā)展,但缺氧究竟影響了乙酰膽堿系統(tǒng)的哪些環(huán)節(jié),還有待進(jìn)一步闡明。 本課題第一部分通過(guò)大鼠腦皮層神經(jīng)元培養(yǎng)并予缺氧處理,在培養(yǎng)液中分別添加抑制性氨基酸γ-氨基丁酸、甘氨酸和牛磺酸進(jìn)行刺激,測(cè)定GABA受體(GABA_ARα1)和glycine受體(GlyRα1)密度,以研究抑制性氨基酸對(duì)這兩種受體的影響。 另外,文獻(xiàn)報(bào)道,δ阿片受體(δ-opioid receptor,DOR)對(duì)腦缺氧/缺血具有保護(hù)作用。本課題第二、第三部分借助于本實(shí)驗(yàn)室建立的DOR轉(zhuǎn)基因小鼠,經(jīng)缺氧處理后,觀察大腦皮層神經(jīng)元中GABA受體及ChAT表達(dá)的變化,探討缺氧和轉(zhuǎn)基因DOR對(duì)GABA受體及ChAT的影響。 第一部分抑制性氨基酸對(duì)發(fā)育中缺氧性皮質(zhì)神經(jīng)元γ-氨基丁酸和甘氨酸受體表達(dá)影響的研究 目的:研究抑制性氨基酸對(duì)發(fā)育中缺氧性皮層神經(jīng)元γ-氨基丁酸和甘氨酸受體表達(dá)的影響。 方法:取妊娠17-18天的胚胎大鼠腦皮層神經(jīng)元原代培養(yǎng),給予1%氧進(jìn)行缺氧處理;在細(xì)胞培養(yǎng)液中,分別用不同濃度(10-2000μM)的抑制性氨基酸γ-氨基丁酸(GABA)、甘氨酸(glycine)和�；撬�(taurine)于體外培養(yǎng)的第4天(DIV4)和20天(DIV20)兩個(gè)時(shí)間點(diǎn)進(jìn)行添加刺激;此外,分別在DIV4和DIV20時(shí)使用腦啡肽(DADLE,一種DOR激動(dòng)劑)刺激。用Western blot方法測(cè)定細(xì)胞中GABA_ARα1和GlyRα1蛋白密度。 結(jié)果:(1)在體外生長(zhǎng)發(fā)育的皮層神經(jīng)元中,GABA_ARα1和GlyRα1的表達(dá)有變化,即在未發(fā)育成熟(DIV4)神經(jīng)元中,GABA_ARα1表達(dá)較低,隨著培養(yǎng)時(shí)間的延長(zhǎng),表達(dá)逐漸增加;GlyRα1表達(dá)在神經(jīng)元發(fā)育早期已達(dá)成熟期的較高水平。(2)缺氧提高了未成熟神經(jīng)元GABA_ARα1和GlyRα1的表達(dá),而降低了GABA_ARα1和GlyRα1在成熟神經(jīng)元的表達(dá)。(3)常氧狀態(tài)下,GABA和glycine傾向于降低未成熟神經(jīng)元GABA_ARα1和GlyRα1表達(dá),但促進(jìn)了發(fā)育成熟神經(jīng)元的表達(dá)。(4)缺氧時(shí),GABA,glycine和taurine降低了GABA_ARα1和GlyRα1在未成熟神經(jīng)元中的表達(dá),而對(duì)成熟神經(jīng)元,則抵御了缺氧引起的受體表達(dá)下降。(5)δ阿片受體(δ-opioid receptor,DOR)的激活促進(jìn)了GABA_ARα1和GlyRα1在常氧狀態(tài)下成熟和未成熟神經(jīng)元以及缺氧狀態(tài)下成熟神經(jīng)元中的表達(dá)。 結(jié)論:抑制性氨基酸對(duì)未成熟神經(jīng)元由于其細(xì)胞毒性作用,降低了GABA_ARα1和GlyRα1在常氧和缺氧時(shí)的表達(dá);而對(duì)成熟神經(jīng)元,防止了缺氧引起的受體表達(dá)下降,并在常氧時(shí)保護(hù)了皮層細(xì)胞,同時(shí)上調(diào)了GABA_ARα1和GlyRα1表達(dá);DOR有細(xì)胞保護(hù)作用,并提高了GABA_ARα1和GlyRα1表達(dá)。 第二部分慢性缺氧對(duì)DOR轉(zhuǎn)基因小鼠腦內(nèi)膽堿乙酰轉(zhuǎn)移酶(ChAT)影響的研究 目的:用轉(zhuǎn)基因增加DOR(δ-opioid receptor)表達(dá)的方式,研究慢性缺氧狀態(tài)下小鼠腦內(nèi)膽堿乙酰轉(zhuǎn)移酶(ChAT)表達(dá)的變化,了解DOR對(duì)膽堿能神經(jīng)元的作用。 方法:對(duì)成年(30日齡)和發(fā)育晚期(20日齡)之DOR轉(zhuǎn)基因和野生型小鼠分別進(jìn)行1天、3天、5天和7天缺氧(10%氧濃度)處理,取其皮層、皮層下、海馬、腦干和小腦5個(gè)部位腦組織,用Western blot方法測(cè)定ChAT水平。 結(jié)果:在常氧環(huán)境中,DOR轉(zhuǎn)基因鼠4個(gè)腦區(qū)(皮層、皮層下、海馬、腦干)中ChAT密度明顯低于野生型鼠;慢性缺氧(7天)使野生型鼠腦皮層、海馬和腦干內(nèi)ChAT密度降低,而同樣慢性缺氧后,DOR轉(zhuǎn)基因鼠上述腦區(qū)ChAT密度不但不下降,相反有增加趨勢(shì)。 結(jié)論:缺氧降低了野生型小鼠腦內(nèi)ChAT表達(dá)水平。而在轉(zhuǎn)基因小鼠,由于DOR的高表達(dá),防止了缺氧誘發(fā)的ChAT下降,提示DOR對(duì)缺氧狀態(tài)下的膽堿能神經(jīng)元具有保護(hù)作用。 第三部分缺氧對(duì)DOR轉(zhuǎn)基因小鼠腦皮層神經(jīng)元GABA_A受體表達(dá)影響的研究 目的:通過(guò)對(duì)DOR(δ-opioid receptor)轉(zhuǎn)基因小鼠和野生型小鼠在缺氧和常氧狀態(tài)下皮層神經(jīng)元中GABA_A受體的研究,從整體動(dòng)物水平了解缺氧和轉(zhuǎn)基因DOR對(duì)大腦皮層神經(jīng)元GABAA受體表達(dá)的影響,進(jìn)一步探索DOR的神經(jīng)保護(hù)作用。 方法:將DOR轉(zhuǎn)基因小鼠和野生型小鼠分為缺氧組和常氧組(非缺氧組),對(duì)缺氧組分別施以1天、3天、5天和7天缺氧(10%氧濃度)處理。取其大腦皮層組織,提取蛋白質(zhì),周Western blot方法測(cè)定其GABA_A受體(GABA_ARα1)水平。 結(jié)果:在常氧環(huán)境,DOR轉(zhuǎn)基因小鼠大腦皮層中GABA_ARα1密度傾向于較野生型鼠為低,慢性缺氧后這種差異更加明顯(P＜0.05);經(jīng)過(guò)1—7天的缺氧,野生型小鼠大腦皮層中GABA_ARα1表達(dá)無(wú)明顯變化。 結(jié)論:轉(zhuǎn)基因小鼠腦皮層中GABA_ARα1表達(dá)低于野生型小鼠;慢性缺氧進(jìn)一步下調(diào)了轉(zhuǎn)基因小鼠腦皮層神經(jīng)元之GABA_ARα1表達(dá);轉(zhuǎn)基因DOR的存在,可能抑制了小鼠腦皮層神經(jīng)元中GABA_ARα1的表達(dá);7天時(shí)間的缺氧未能引起野生型小鼠腦內(nèi)GABA_ARα1表達(dá)變化。
[Abstract]:Hypoxia is a common clinical pathological phenomenon, which can lead to a variety of hypoxic diseases, involving respiratory, nervous, cardiovascular and many other fields.
After brain tissue hypoxia, ATP production is insufficient, acidosis, membrane ion transport disorders, membrane potential changes and so on, resulting in decreased neurotransmitter synthesis and abnormal receptor expression. These functional proteins affect synaptic transmission, leading to changes in brain cell function and structure.
Amino acid neurotransmitters are important neurotransmitters in the brain.The normal function of brain cells depends on the balance between excitatory and inhibitory amino acids.Glutamic acid and aspartate are the representatives of the former,which mediate most of the rapid excitatory synaptic transmission,while GABA and glycine are the representatives of the latter. Recent studies have shown that inhibitory amino acids play an important role in protecting brain cells against hypoxia/ischemia and other stress responses, and that inhibitory amino acids play different roles in neurons of different developmental stages. The expression of the body and the effect of inhibitory amino acids on the expression of these two receptors are not clear.
Another important transmitter system in the brain is the acetylcholine system, which is involved in the transmission of information between movement and sensory processes. Because choline acetyltransferase (ChAT) is the rate-limiting enzyme for acetylcholine synthesis, its abnormalities are closely related to disease s such as Alzheimer's disease (AD). Alkali metabolism is involved in the occurrence and development of Alzheimer's disease, but what links of the acetylcholine system are affected by hypoxia remains to be further clarified.
In the first part of this study, the inhibiting amino acids gamma-aminobutyric acid, glycine and taurine were added to the culture medium to stimulate the cultured cortical neurons of rats. The density of GABA receptor (GABA_AR_ alpha1) and glycine receptor (GlyR_ alpha1) were measured to study the effect of inhibiting amino acids on the two receptors.
In addition, it has been reported that delta-opioid receptor (DOR) has protective effects on cerebral hypoxia/ischemia. In the second and third part of this study, the expression of GABA receptor and ChAT in cerebral cortex neurons was observed in hypoxic-treated DOR transgenic mice, and the effects of hypoxia and transgenic DOR on GABA receptor and C-hAT were investigated. The impact of hAT.
Part I Effects of Inhibitory Amino Acids on the Expression of Gamma-aminobutyric Acid and Glycine Receptors in Developing Hypoxic Cortical Neurons
AIM: To investigate the effects of inhibitory amino acids on the expression of gamma-aminobutyric acid and glycine receptors in developing hypoxic cortical neurons.
METHODS: The primary cultured cortical neurons of embryonic rats from 17 to 18 days of gestation were given 1% oxygen for hypoxia treatment, and the inhibitory amino acids gamma-aminobutyric acid (GABA), glycine and taurine (GABA) of different concentrations (10-2000 mu M) were used in the culture medium for the 4th day (DIV4) and 20th day (DIV20) respectively. In addition, enkephalin (DADLE, a DOR agonist) was used to stimulate DIV4 and DIV20, respectively. The density of GABA_AR_ alpha1 and GlyR_ alpha1 proteins was determined by Western blot.
Results: (1) The expression of GABA_AR_ alpha1 and GlyR_ alpha1 was changed in cortical neurons which grew in vitro, that is, the expression of GABA_AR_ alpha1 was lower in immature (DIV4) neurons, and increased gradually with the prolongation of culture time; the expression of GlyR_ alpha1 reached a higher level in the early stage of neuronal development. (2) Hypoxia increased the immature (DIV4) The expression of GABA_AR_ alpha1 increased gradually. The expression of GABA_AR alpha1 and GlyR alpha1 in neurons decreased, while the expression of GABA_AR alpha1 and GlyR alpha1 in mature neurons decreased. (3) Under normoxia, GABA and glycine tended to decrease the expression of GABA_AR alpha1 and GlyR alpha1 in immature neurons, but promoted the expression of mature neurons. (4) Under hypoxia, GABA, glycine and taurine decreased the expression of GABA_AR alpha1 and GlyR alpha1 in mature neurons. (5) The activation of delta-opioid receptor (DOR) promotes the expression of GABA_AR_ alpha 1 and GlyR_ alpha 1 in mature and immature neurons under normoxia and hypoxia.
CONCLUSION: Inhibitory amino acids can decrease the expression of GABA_AR_ alpha1 and GlyR_ alpha1 in immature neurons under normoxia and hypoxia due to their cytotoxic effects, while DOR can protect mature neurons from hypoxia-induced decrease of receptor expression and protect cortical cells under normoxia, and up-regulate the expression of GABA_AR_ alpha1 and GlyR_ alpha1. The expression of GABA_AR alpha 1 and GlyR alpha 1 was increased.
The second part is the effect of chronic hypoxia on the brain cholinyl acetyltransferase (ChAT) in DOR transgenic mice.
AIM: To study the expression of cholinergic acetyltransferase (ChAT) in the brain of mice under chronic hypoxia and to understand the effect of DOR on cholinergic neurons.
METHODS: Hypoxia (10% oxygen concentration) was performed on day 1, day 3, day 5 and day 7 in adult (30 days old) and late developmental (20 days old) DOR transgenic and wild type mice, respectively. The levels of ChAT in cortex, subcortex, hippocampus, brainstem and cerebellum were measured by Western blot.
Results: The ChAT density in four brain regions (cortex, subcortex, hippocampus and brainstem) of DOR transgenic mice was significantly lower than that of wild type mice in normoxic environment; the ChAT density in the cortex, hippocampus and brainstem of wild type mice was decreased by chronic hypoxia (7 days), but the ChAT density in the above brain regions of DOR transgenic mice did not decrease after the same chronic hypoxia.
CONCLUSION: Hypoxia decreases the expression of ChAT in the brain of wild type mice, but in transgenic mice, the high expression of DOR prevents hypoxia-induced decrease of ChAT, suggesting that DOR has protective effect on cholinergic neurons under hypoxia.
The third part is the effect of hypoxia on the expression of GABA_A receptor in cortical neurons of DOR transgenic mice.
AIM: To investigate the effects of hypoxia and transgenic DOR on the expression of GABAA receptors in cerebral cortical neurons and explore the neuroprotective effect of DOR.
Methods: DOR transgenic mice and wild type mice were divided into hypoxic group and normoxic group (non-hypoxic group). The hypoxic group was treated with hypoxia (10% oxygen concentration) for 1 day, 3 days, 5 days and 7 days, respectively. The cerebral cortex was extracted and the levels of GABA_A receptor (GABA_AR alpha 1) were determined by Western blot.
Results: In normal oxygen environment, the density of GABA_AR alpha 1 in the cerebral cortex of DOR transgenic mice tended to be lower than that of wild type mice, and the difference was more obvious after chronic hypoxia (P < 0.05).
CONCLUSION: The expression of GABA_AR alpha1 in the cerebral cortex of transgenic mice is lower than that of wild-type mice; chronic hypoxia further down-regulates the expression of GABA_AR alpha1 in the cerebral cortex of transgenic mice; the presence of transgenic DOR may inhibit the expression of GABA_AR alpha1 in the cerebral cortex neurons of mice; 7-day hypoxia does not induce GABA_AR alpha1 in the brain of wild-type mice. The expression of alpha 1 was changed.
【學(xué)位授予單位】：南京醫(yī)科大學(xué)
【學(xué)位級(jí)別】：博士
【學(xué)位授予年份】：2008
【分類號(hào)】：R363
本文編號(hào)：2233720
[Abstract]:Hypoxia is a common clinical pathological phenomenon, which can lead to a variety of hypoxic diseases, involving respiratory, nervous, cardiovascular and many other fields.
After brain tissue hypoxia, ATP production is insufficient, acidosis, membrane ion transport disorders, membrane potential changes and so on, resulting in decreased neurotransmitter synthesis and abnormal receptor expression. These functional proteins affect synaptic transmission, leading to changes in brain cell function and structure.
Amino acid neurotransmitters are important neurotransmitters in the brain.The normal function of brain cells depends on the balance between excitatory and inhibitory amino acids.Glutamic acid and aspartate are the representatives of the former,which mediate most of the rapid excitatory synaptic transmission,while GABA and glycine are the representatives of the latter. Recent studies have shown that inhibitory amino acids play an important role in protecting brain cells against hypoxia/ischemia and other stress responses, and that inhibitory amino acids play different roles in neurons of different developmental stages. The expression of the body and the effect of inhibitory amino acids on the expression of these two receptors are not clear.
Another important transmitter system in the brain is the acetylcholine system, which is involved in the transmission of information between movement and sensory processes. Because choline acetyltransferase (ChAT) is the rate-limiting enzyme for acetylcholine synthesis, its abnormalities are closely related to disease s such as Alzheimer's disease (AD). Alkali metabolism is involved in the occurrence and development of Alzheimer's disease, but what links of the acetylcholine system are affected by hypoxia remains to be further clarified.
In the first part of this study, the inhibiting amino acids gamma-aminobutyric acid, glycine and taurine were added to the culture medium to stimulate the cultured cortical neurons of rats. The density of GABA receptor (GABA_AR_ alpha1) and glycine receptor (GlyR_ alpha1) were measured to study the effect of inhibiting amino acids on the two receptors.
In addition, it has been reported that delta-opioid receptor (DOR) has protective effects on cerebral hypoxia/ischemia. In the second and third part of this study, the expression of GABA receptor and ChAT in cerebral cortex neurons was observed in hypoxic-treated DOR transgenic mice, and the effects of hypoxia and transgenic DOR on GABA receptor and C-hAT were investigated. The impact of hAT.
Part I Effects of Inhibitory Amino Acids on the Expression of Gamma-aminobutyric Acid and Glycine Receptors in Developing Hypoxic Cortical Neurons
AIM: To investigate the effects of inhibitory amino acids on the expression of gamma-aminobutyric acid and glycine receptors in developing hypoxic cortical neurons.
METHODS: The primary cultured cortical neurons of embryonic rats from 17 to 18 days of gestation were given 1% oxygen for hypoxia treatment, and the inhibitory amino acids gamma-aminobutyric acid (GABA), glycine and taurine (GABA) of different concentrations (10-2000 mu M) were used in the culture medium for the 4th day (DIV4) and 20th day (DIV20) respectively. In addition, enkephalin (DADLE, a DOR agonist) was used to stimulate DIV4 and DIV20, respectively. The density of GABA_AR_ alpha1 and GlyR_ alpha1 proteins was determined by Western blot.
Results: (1) The expression of GABA_AR_ alpha1 and GlyR_ alpha1 was changed in cortical neurons which grew in vitro, that is, the expression of GABA_AR_ alpha1 was lower in immature (DIV4) neurons, and increased gradually with the prolongation of culture time; the expression of GlyR_ alpha1 reached a higher level in the early stage of neuronal development. (2) Hypoxia increased the immature (DIV4) The expression of GABA_AR_ alpha1 increased gradually. The expression of GABA_AR alpha1 and GlyR alpha1 in neurons decreased, while the expression of GABA_AR alpha1 and GlyR alpha1 in mature neurons decreased. (3) Under normoxia, GABA and glycine tended to decrease the expression of GABA_AR alpha1 and GlyR alpha1 in immature neurons, but promoted the expression of mature neurons. (4) Under hypoxia, GABA, glycine and taurine decreased the expression of GABA_AR alpha1 and GlyR alpha1 in mature neurons. (5) The activation of delta-opioid receptor (DOR) promotes the expression of GABA_AR_ alpha 1 and GlyR_ alpha 1 in mature and immature neurons under normoxia and hypoxia.
CONCLUSION: Inhibitory amino acids can decrease the expression of GABA_AR_ alpha1 and GlyR_ alpha1 in immature neurons under normoxia and hypoxia due to their cytotoxic effects, while DOR can protect mature neurons from hypoxia-induced decrease of receptor expression and protect cortical cells under normoxia, and up-regulate the expression of GABA_AR_ alpha1 and GlyR_ alpha1. The expression of GABA_AR alpha 1 and GlyR alpha 1 was increased.
The second part is the effect of chronic hypoxia on the brain cholinyl acetyltransferase (ChAT) in DOR transgenic mice.
AIM: To study the expression of cholinergic acetyltransferase (ChAT) in the brain of mice under chronic hypoxia and to understand the effect of DOR on cholinergic neurons.
METHODS: Hypoxia (10% oxygen concentration) was performed on day 1, day 3, day 5 and day 7 in adult (30 days old) and late developmental (20 days old) DOR transgenic and wild type mice, respectively. The levels of ChAT in cortex, subcortex, hippocampus, brainstem and cerebellum were measured by Western blot.
Results: The ChAT density in four brain regions (cortex, subcortex, hippocampus and brainstem) of DOR transgenic mice was significantly lower than that of wild type mice in normoxic environment; the ChAT density in the cortex, hippocampus and brainstem of wild type mice was decreased by chronic hypoxia (7 days), but the ChAT density in the above brain regions of DOR transgenic mice did not decrease after the same chronic hypoxia.
CONCLUSION: Hypoxia decreases the expression of ChAT in the brain of wild type mice, but in transgenic mice, the high expression of DOR prevents hypoxia-induced decrease of ChAT, suggesting that DOR has protective effect on cholinergic neurons under hypoxia.
The third part is the effect of hypoxia on the expression of GABA_A receptor in cortical neurons of DOR transgenic mice.
AIM: To investigate the effects of hypoxia and transgenic DOR on the expression of GABAA receptors in cerebral cortical neurons and explore the neuroprotective effect of DOR.
Methods: DOR transgenic mice and wild type mice were divided into hypoxic group and normoxic group (non-hypoxic group). The hypoxic group was treated with hypoxia (10% oxygen concentration) for 1 day, 3 days, 5 days and 7 days, respectively. The cerebral cortex was extracted and the levels of GABA_A receptor (GABA_AR alpha 1) were determined by Western blot.
Results: In normal oxygen environment, the density of GABA_AR alpha 1 in the cerebral cortex of DOR transgenic mice tended to be lower than that of wild type mice, and the difference was more obvious after chronic hypoxia (P < 0.05).
CONCLUSION: The expression of GABA_AR alpha1 in the cerebral cortex of transgenic mice is lower than that of wild-type mice; chronic hypoxia further down-regulates the expression of GABA_AR alpha1 in the cerebral cortex of transgenic mice; the presence of transgenic DOR may inhibit the expression of GABA_AR alpha1 in the cerebral cortex neurons of mice; 7-day hypoxia does not induce GABA_AR alpha1 in the brain of wild-type mice. The expression of alpha 1 was changed.
【學(xué)位授予單位】：南京醫(yī)科大學(xué)
【學(xué)位級(jí)別】：博士
【學(xué)位授予年份】：2008
【分類號(hào)】：R363
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