本文選題：肌萎縮側(cè)索硬化 + 臨床表現(xiàn)　； 參考：《山東大學(xué)》2017年博士論文

【摘要】：肌萎縮側(cè)索硬化(amyotrophic lateral sclerosis,ALS)是成人運(yùn)動神經(jīng)元病最常見的類型,由Charcot于1869年首先描述。ALS與其他運(yùn)動神經(jīng)元病的區(qū)別是上運(yùn)動神經(jīng)元和下運(yùn)動神經(jīng)元均發(fā)生變性。ALS主要的神經(jīng)病理特征包括脊髓前角及腦干運(yùn)動神經(jīng)元廣泛損失、皮質(zhì)脊髓束變性和初級運(yùn)動皮質(zhì)大錐體神經(jīng)元變性及損失。ALS的患病率約為5-7/10萬,大多數(shù)ALS病例為散發(fā)性(sALS),5-10%為家族性(fALS)。無論患者是散發(fā)性還是家族性,均會發(fā)生進(jìn)行性肌肉無力和肌肉萎縮。進(jìn)行性肌肉無力可始于上肢或下肢的近端或遠(yuǎn)端,并可累及所有肌肉,包括與呼吸、言語及吞咽有關(guān)的肌肉。多數(shù)患者在被診斷2-5年后,死于呼吸衰竭。在疾病早期,下運(yùn)動神經(jīng)元和上運(yùn)動神經(jīng)元受累的不同模式使ALS的診斷面臨挑戰(zhàn)。由于ALS最初癥狀與其他脊髓疾病、周圍神經(jīng)病變及神經(jīng)綜合征相似,因而診斷延遲是其主要問題之一。由于缺乏特異的疾病標(biāo)志,ALS臨床診斷標(biāo)準(zhǔn)的建立基于下運(yùn)動神經(jīng)元和上運(yùn)動神經(jīng)元病變的存在及分布,并且需要使用排除過程來確定診斷。實(shí)驗(yàn)室檢查、神經(jīng)影像和肌肉活檢都可能有助于鑒別診斷和排除與ALS類似的疾病過程,而一旦其他疾病過程被排除,電生理評估是確立ALS診斷的關(guān)鍵。并且,電生理評價(jià)不僅在疾病診斷中有用,而且有助于監(jiān)測疾病的進(jìn)展和對干預(yù)的反應(yīng),有助于確定預(yù)后。因此,目前ALS診斷主要依靠臨床表現(xiàn)與神經(jīng)電生理檢查相結(jié)合。目前被識別的引起ALS的基因突變超過20種,其中最常見的突變發(fā)生于SOD1、RNA結(jié)合蛋白編碼基因TARDBP、FUS,以及最近所認(rèn)識C9orf72基因。2011年,C9orf72基因非編碼區(qū)六核苷酸GGGGCC的致病性重復(fù)擴(kuò)增現(xiàn)象在ALS和額顳葉癡呆患者中被發(fā)現(xiàn)并報(bào)道。通過對9p21位點(diǎn)上風(fēng)險(xiǎn)單倍型的研究認(rèn)識到C9orf72基因中GGGGCC擴(kuò)增。應(yīng)用重復(fù)引物聚合酶鏈反應(yīng)的測序,最終認(rèn)為至少30次的重復(fù)擴(kuò)增與ALS有關(guān)。與非C9orf72 ALS病例相比,C9orf72相關(guān)性ALS有其臨床特征,伴發(fā)額顳葉癡呆的比例明顯增高,容易出現(xiàn)認(rèn)知功能障礙和精神行為異常,延髓起病的比例增高,發(fā)病年齡提前1.8-5.0年,運(yùn)動癥狀惡化速度快,病程縮短5.7-12.0月,顯示了其更強(qiáng)的疾病進(jìn)程。同時(shí),C9orf72疾病譜還包括原發(fā)性側(cè)索硬化、進(jìn)行性肌萎縮、帕金森綜合征/帕金森病、亨廷頓病、阿爾茨海默病等。由于攜帶C9orf72基因突變的患者數(shù)量眾多,并且C9orf72相關(guān)疾病譜非常廣泛,其介導(dǎo)的ALS是多方面且復(fù)雜的,近年來C9orf72基因逐漸成為研究熱點(diǎn)。核因子κB(nuclear factor kappa B,NF-κB)是淋巴細(xì)胞中的一種誘導(dǎo)型轉(zhuǎn)錄因子,對身體中幾乎所有細(xì)胞類型都產(chǎn)生影響,在炎癥、免疫反應(yīng)、細(xì)胞周期和細(xì)胞存活中起重要作用。在中樞神經(jīng)系統(tǒng),NF-κB轉(zhuǎn)錄因子是神經(jīng)發(fā)生、神經(jīng)突生成及突觸可塑性等許多生理過程的關(guān)鍵參與者。NF-κB為組成型活性,參與神經(jīng)元細(xì)胞體中的神經(jīng)元損傷以及神經(jīng)保護(hù)。NF-1κB在突觸中以潛在形式存在,只有當(dāng)其被激活時(shí),才能被運(yùn)輸?shù)缴窠?jīng)元細(xì)胞核。免疫組化證實(shí),NF-κB可在家族和散發(fā)ALS患者的神經(jīng)膠質(zhì)中被活化。研究表明,SOD1-G93A小膠質(zhì)細(xì)胞在NF-κB依賴性機(jī)制中在體內(nèi)及體外均可誘導(dǎo)運(yùn)動神經(jīng)元死亡。第一部分肌萎縮側(cè)索硬化的臨床及電生理特點(diǎn)分析目的:通過分析ALS臨床及電生理資料,為臨床醫(yī)生提供本病較為直觀和深入的認(rèn)識,使患者盡可能得到早期診斷,從而獲得正確的治療,以期患者的生存期得以延長,生活質(zhì)量得以提高。方法:收集2009年1月至2016年6月在我院神經(jīng)內(nèi)科就診的73例患者,符合E1 Escorial修訂版診斷標(biāo)準(zhǔn),診斷分級為臨床確診及臨床擬診。進(jìn)行詳盡的病史詢問及神經(jīng)查體,收集患者的發(fā)病年齡、起病部位、累及部位、主要的癥狀及體征,進(jìn)行運(yùn)動傳導(dǎo)速度(motor conduction velocity,MCV)測定、感覺傳導(dǎo)速度(sensory conduction velocity,SCV)測定、重復(fù)神經(jīng)刺激(repetitive nerve stimulation,RNS)、針電極肌電圖(EMG)等電生理檢查,回顧性分析、總結(jié)ALS的臨床及電生理特點(diǎn)。結(jié)果:患者共73例,其中男42例(57.5%),女性31例(42.5%),男女比例為1.4:1。發(fā)病年齡28.1-78.8歲,平均發(fā)病年齡(51.7±12.4)歲。發(fā)病年齡高峰為51-60歲。起病部位比率最高的頸段為56.2%,其次為腰骶段(24.6%)和延髓段(19.2%)。常見的下運(yùn)動神經(jīng)元癥狀及體征中肌肉無力(97.3%)和肌肉萎縮(76.7%)最常見。運(yùn)動神經(jīng)傳導(dǎo)總的異常率為45.9%,但運(yùn)動傳導(dǎo)的遠(yuǎn)端潛伏期、波幅及傳導(dǎo)速度的平均值均在正常范圍。復(fù)合肌肉動作電位(compound muscle action potential,CMAP)波幅值與截?cái)嘀档谋戎?正中神經(jīng)平均值為(1.06±0.74),尺神經(jīng)平均值為(1.49±0.81),尺神經(jīng)明顯大于正中神經(jīng)(P=0.000)。感覺神經(jīng)傳導(dǎo)總的異常率為2.3%,但感覺傳導(dǎo)的波幅及傳導(dǎo)速度的平均值均在正常范圍。重復(fù)神經(jīng)刺激,拇短展肌(正中神經(jīng)支配)和小指展肌(尺神經(jīng)支配)記錄的CMAP波幅遞減的平均值分別為(9.07%±8.68%)和(2.89%±2.47%),拇短展肌的遞減幅度明顯大于小指展肌(P=0.000)。在正中神經(jīng),CMAP遞減和CMAP的波幅呈負(fù)相關(guān)(R=-0.357,P=0.000),而在尺神經(jīng),沒有觀察到相關(guān)性(P=0.223)。針電極EMG顯示,舌肌總的自發(fā)電位及纖顫/正尖波、束顫電位的出現(xiàn)率(分別為 79.1%、65.1%、58.1%)均比胸鎖乳突肌(分別為 48.8%、30.2%、32.6%)高(P值分別為0.004,0.001,0.017)。具有延髓癥狀和僅具肢體癥狀的患者,其舌肌自發(fā)電位的出現(xiàn)率分別為84.2%和75.0%,二者相比無統(tǒng)計(jì)學(xué)差異(P=0.708)。結(jié)論:ALS發(fā)病男性多于女性,好發(fā)于中老年人,發(fā)病高峰為51-60歲。起病部位以頸段最多,其次為腰骶段、延髓段。下運(yùn)動神經(jīng)元癥狀以肌肉無力最多見,其次為肌肉萎縮。部分患者會出現(xiàn)運(yùn)動傳導(dǎo)異常,以CMAP波幅下降最為多見。感覺傳導(dǎo)異常少見,說明本病對感覺傳導(dǎo)通路影響不大;如果出現(xiàn)異常,并不能完全排除本病,應(yīng)注意排除伴隨的其他周圍神經(jīng)病。RNS檢查表明,正中神經(jīng)比尺神經(jīng)CMAP波幅遞減的幅度大,其原因是在ALS的病理生理中正中神經(jīng)較尺神經(jīng)優(yōu)先受累。CMAP遞減可能由新芽生的神經(jīng)末梢傳導(dǎo)不穩(wěn)定引起。在評估舌肌的臨床和亞臨床受累方面,無論是延髓起病還是肢體起病的ALS,舌肌針電極EMG均是一種有價(jià)值的電生理方法,但應(yīng)注意操作方法。第二部分ALS突變基因C9orf72細(xì)胞模型的生物學(xué)功能分析及其機(jī)制的研究目的:構(gòu)建C9orf72誘導(dǎo)的ALS細(xì)胞模型并對其進(jìn)行生物學(xué)功能分析;檢測C9orf72是否通過NF-κB信號通路造成神經(jīng)元損傷。方法:利用化學(xué)合成方法,體外獲得C9orf72的突變基因,然后構(gòu)建基因的真核表達(dá)載體;應(yīng)用陽離子脂質(zhì)體轉(zhuǎn)染法,將上述構(gòu)建成功的真核表達(dá)載體轉(zhuǎn)染到NSC-34細(xì)胞中,使用RT-PCR和Western blots方法,分別在轉(zhuǎn)錄組與蛋白質(zhì)組進(jìn)行檢測,確認(rèn)細(xì)胞模型構(gòu)建成功;使用免疫細(xì)胞化學(xué)方法,進(jìn)行神經(jīng)元細(xì)胞的形態(tài)學(xué)檢測;使用丙二醛(MDA)方法,檢測細(xì)胞氧化應(yīng)激情況;實(shí)驗(yàn)組與對照組,應(yīng)用RT-PCR和Western blots方法,進(jìn)行NF-κB信號通路活性檢測;將siRNA-NF-κB轉(zhuǎn)染到NSC-34細(xì)胞中,應(yīng)用Western blots方法,研究NF-κB信號通路中,實(shí)驗(yàn)組與對照組的上下游蛋白分子變化,根據(jù)變化情況去闡明C9orf72誘導(dǎo)的ALS發(fā)生的分子機(jī)制。結(jié)果:獲得轉(zhuǎn)染 pcDNA3.1(+)-(CATCATCACCATCACCAT)(GGGGCC)30 成功的細(xì)胞模型。免疫細(xì)胞化學(xué)檢測發(fā)現(xiàn),與對照組相比,轉(zhuǎn)染pcDNA3.1(+)-(CATCATCACCATCACCAT)(GGGGCC)30 后,胞體明顯變圓,突起減少,且軸突變短。MDA結(jié)果顯示,轉(zhuǎn)染組為(2.92±0.14)nmol/mgprot,正常組為(1.63±0.12)nmol/mgprot,空載組為(1.82±0.21)nmol/mgprot,轉(zhuǎn)染組細(xì)胞內(nèi)MDA的含量明顯高于其他兩組(P0.05)。轉(zhuǎn)染pcDNA3.1(+)-(CATCATCACCATCACCAT)(GGGGCC)30 24 小時(shí)后,以正常細(xì)胞組和轉(zhuǎn)染pcDNA3.1(+)組作為對照組,與對照組相比較,轉(zhuǎn)染組中細(xì)胞內(nèi)的P-NF-κB蛋白表達(dá)明顯升高(P0.05)。轉(zhuǎn)染siRNA-NF-κB 24小時(shí)后,與siRNA轉(zhuǎn)染組相比較,siRNA-NF-KB轉(zhuǎn)染組中細(xì)胞內(nèi)的NF-κB表達(dá)受到明顯的抑制(P0.05);但是C9orf72蛋白的表達(dá)無變化。正常組、空載體組、pcDNA3.1(+)-(CATCATCACCATCACCAT)(GGGGCC)30 轉(zhuǎn)染組與 siRNA-NF-κB轉(zhuǎn)染組的 MDA 含量分別為(1.72±0.22)nmol/mgprot、(1.86±0.37)nmol/mgprot、(3.12±0.28)nmol/mgprot、(1.75±0.18)nmol/mgprot。統(tǒng)計(jì)學(xué)分析顯示,pcDNA3.1(+)-(CATCATCACCATCACCAT)(GGGGCC)30 轉(zhuǎn)染組細(xì)胞內(nèi)的 MDA含量明顯高于其他三組細(xì)胞(P0.05),而siRNA-NF-KB轉(zhuǎn)染組的MDA含量與正常組和空載體組相比沒有明顯差異(P0.05)。結(jié)論:本研究成功構(gòu)建了 C9orf72誘導(dǎo)的ALS細(xì)胞模型。C9orf72基因中30次重復(fù)的GGGGCC對神經(jīng)元樣細(xì)胞存在毒性損傷作用。C9orf72通過下游NF-κB信號通路導(dǎo)致神經(jīng)元損傷。
[Abstract]:Amyotrophic lateral sclerosis (amyotrophic lateral sclerosis, ALS) is the most common type of adult motor neuron disease. It was first described by Charcot in 1869 that the difference between.ALS and other motor neuron diseases was that both upper motor and lower motor neurons were the main degenerative.ALS of the degeneration.ALS including the anterior horn of the spinal cord and the deity of the brain stem. The prevalence of.ALS was about 5-7/10 million after extensive loss, corticospinal degeneration, and primary motor cortex major pyramidal neuron degeneration and loss. Most of the ALS cases were sporadic (sALS) and 5-10% was familial (fALS). Progressive muscle weakness and muscular atrophy were found in patients with sporadic or familial, progressive muscle weakness. It can begin at the proximal or distal end of the upper or lower limbs and can involve all muscles, including the muscles associated with respiration, speech, and swallowing. Most patients die of respiratory failure after 2-5 years of diagnosis. In the early stages of the disease, the different patterns of the involvement of the motor neurons and the upper motor neurons in the early stage of the disease challenge the diagnosis of ALS. Because of the initial symptoms of ALS, His spinal cord disease, peripheral neuropathy, and neurologic syndrome are similar, so the diagnosis delay is one of the major problems. Due to the lack of specific disease markers, the establishment of the ALS clinical diagnostic criteria is based on the presence and distribution of the lower motor neuron and upper motor neuron disease, and needs to use the exclusion process to determine the diagnosis. Laboratory examination, Neuroimaging and muscle biopsy may help identify and exclude the process of disease similar to ALS, and electrophysiological assessment is the key to the establishment of a ALS diagnosis once other disease processes are excluded. And electrophysiological evaluation is not only useful in the diagnosis of disease but also helps to monitor the progress of the disease and the response to intervention. Therefore, the current ALS diagnosis relies mainly on the combination of clinical and neuroelectrophysiological tests. The current identification of ALS gene mutations is more than 20, of which the most common mutations occur in SOD1, RNA binding protein encoding gene TARDBP, FUS, and the recent recognition of the C9orf72 gene.2011, and the non coding region six nucleosides of the C9orf72 gene. The pathogenicity repeat amplification of acid GGGGCC was found in ALS and patients with frontoleaf dementia. The GGGGCC amplification in the C9orf72 gene was recognized by the study of the risk haplotype at the 9p21 locus. The sequence of repeated primer polymerase chain reaction was used to conclude that at least 30 repeated amplification was associated with ALS. C9orf72 related ALS has its clinical features, a significant increase in the proportion of frontotemporal dementia, the incidence of cognitive dysfunction and abnormal mental behavior, the increase in the proportion of the onset of the medulla, the age of 1.8-5.0 in advance, the rapid deterioration of motor symptoms, and the duration of the disease for 5.7-12.0 months, showing a stronger disease process. At the same time, C9orf72 disease The disease also includes primary sclerosis, progressive myosclerosis, Parkinson's syndrome / Parkinson's disease, Huntington's disease, Alzheimer's disease, and so on. The number of patients with the C9orf72 gene mutation is numerous, and the spectrum of C9orf72 related diseases is very extensive. The ALS is multidimensional and complex. In recent years, the C9orf72 gene has gradually become a study. The nuclear factor kappa B (nuclear factor kappa B, NF- kappa B) is an inducible transcription factor in the lymphocyte, which affects almost all types of cells in the body and plays an important role in inflammation, immune response, cell cycle and cell survival. In the central nervous system, the NF- kappa B transcription factor is neurogenesis, neurite production and process. .NF- kappa B, a key participant in many physiological processes such as plasticity, is a constituent activity, participates in neuronal damage in the neuron cell body, and the neuroprotective.NF-1 kappa B exists in the synapse in a potential form only when it is activated can it be transported to the nucleus of the neuron. The immunization of NF- kappa B can be found in the family and in the emission of ALS patients. The study shows that SOD1-G93A microglia can induce the death of motoneurons in the NF- kappa B dependent mechanism in vivo and in vitro. The clinical and electrophysiological characteristics of the first part of amyotrophic lateral sclerosis (amyotrophic lateral sclerosis) are analyzed. By analyzing the clinical and electrophysiological data of ALS, it is more intuitive to provide this disease to clinicians. In order to get the patient to get the early diagnosis as far as possible so as to get the correct treatment so that the patient's life can be prolonged and the quality of life is improved. Methods: 73 patients in the neurology department of our hospital from January 2009 to June 2016 were collected, and the diagnostic criteria of E1 Escorial revision were conformed to the clinical diagnosis and clinical diagnosis. A detailed medical history inquiry and neural examination were carried out to collect the age of the patients, the location of the onset, the areas involved, the main symptoms and signs, the motor conduction velocity (MCV), the sensory conduction velocity (sensory conduction velocity, SCV), and the repetitive nerve stimulation (repetitive nerve stimulation, RN). S), electrophysiological examinations such as needle electrode electromyography (EMG), retrospective analysis, and summary of the clinical and electrophysiological characteristics of ALS. Results: there were 73 patients with 42 males (57.5%) and 31 women (42.5%). The male and female ratio was 28.1-78.8 years of age of 1.4:1., the average age of onset was (51.7 + 12.4) years. The peak of onset age was 51-60 years. The ratio of the onset of the disease was the highest. The cervical segment was 56.2%, followed by the lumbosacral segment (24.6%) and the medulla segment (19.2%). The most common symptoms and signs of the lower motor neurons were muscle weakness (97.3%) and muscle atrophy (76.7%). The total abnormal rate of motor nerve conduction was 45.9%, but the average value of the distal latency, amplitude and conduction velocity of the motor conduction was in the normal range. Complex muscle movement. The ratio of amplitude and truncation value of compound muscle action potential (CMAP), median nerve mean value (1.06 + 0.74), average of ulnar nerve (1.49 + 0.81), and ulnar nerve greater than median nerve (P=0.000). The total abnormal rate of sensory nerve conduction is 2.3%, but the average value of amplitude and conduction velocity of sensory conduction is normal. The average value of CMAP amplitude reduction recorded by repetitive nerve stimulation, abductor abductor muscle (median nerve innervation) and the small digital abductor (ulnar innervation) was (9.07% + 8.68%) and (2.89% + 2.47%), and the decrease of abductor pollicis abductor muscle was significantly greater than that of the small finger abductor muscle (P=0.000). In the median nerve, the decrease of CMAP and the amplitude of CMAP were negatively correlated (R=-0.357, P=0.00). 0) and in the ulnar nerve, no correlation was observed (P=0.223). The needle electrode EMG showed that the total spontaneous potential and fibrillation / positive tip of the tongue muscle were higher than the sternocleidomastoid (48.8%, 30.2%, 32.6%, respectively, 0.004,0.001,0.017, respectively, 65.1%, 65.1%, respectively), with the medullary symptoms and only limb symptoms. The incidence of spontaneous potential of tongue muscle was 84.2% and 75%, respectively, and there was no statistical difference between the two cases (P=0.708). Conclusion: the incidence of ALS is more than that of women. The onset of the onset is in the middle and old age, the peak of the onset is 51-60 years. The most common parts are the neck segment, the second is the lumbosacral segment, the medulla oblongata. Muscle atrophy. Some patients will have abnormal movement conduction with the most frequent decrease of CMAP amplitude. The abnormal sensation conduction is rare, which indicates that the disease has little influence on the sensory conduction pathway; if there is an abnormal occurrence and can not completely exclude the disease, it should be noted that the.RNS examination of the associated peripheral neuropathy should be excluded, and the amplitude of the median nerve CMAP wave should be excluded. The decrease is due to the fact that in the pathophysiology of ALS, the decreasing of the median nerve of the median nerve and the descending of the ulnar nerve may be caused by the instability of the nerve endings of the new buds. In assessing the clinical and subclinical involvement of the tongue muscles, both the medulla and the onset of the limb, the ALS of the lingual muscle needle electrode EMG is a valuable electricity. Physiological methods, but should pay attention to the operation method. Second part of the ALS mutant gene C9orf72 cell model biological function analysis and its mechanism research purpose: to construct the C9orf72 induced ALS cell model and to carry on the biological function analysis; detect whether C9orf72 can cause neuron damage through the NF- kappa B signal pathway. In addition, the mutant gene of C9orf72 was obtained in vitro, then the eukaryotic expression vector of the gene was constructed, and the eukaryotic expression vector was transfected into NSC-34 cells by the cationic liposome transfection method, and the RT-PCR and Western blots methods were used to detect the cells in the transcriptional group and the proteome respectively, confirming the success of the cell model construction. Using the immunocytochemical method, the morphological detection of neuron cells was carried out. The oxidative stress of cells was detected by using MDA method. The experimental group and the control group were used to detect the activity of NF- kappa B signaling pathway by using RT-PCR and Western blots methods; siRNA-NF- kappa B was transfected into NSC-34 cells. Western blots method was used to study NF-. In the kappa B signal pathway, the changes in the upper and lower protein molecules of the experimental group and the control group were changed to elucidate the molecular mechanism of the occurrence of C9orf72 induced ALS. Results: the successful transfection of pcDNA3.1 (+) - (CATCATCACCATCACCAT) (GGGGCC) 30 was a successful cell model. Immunological detection found that the transfection of pcDNA3.1 (+) - (CATCAT) to the control group was compared with the control group. CACCATCACCAT) after (GGGGCC) 30, the cell body became obviously round and the protuberance decreased, and the result of short.MDA showed that the transfection group was (2.92 + 0.14) nmol/mgprot, the normal group was (1.63 + 0.12) nmol/mgprot, and the empty group was (1.82 + 0.21) nmol/mgprot, and the content of MDA in the transfected group was significantly higher than that of the other two groups (P0.05). (GGGGCC) after 3024 hours, the normal cell group and the transfected pcDNA3.1 (+) group were used as the control group. Compared with the control group, the expression of P-NF- kappa B protein in the transfected group was significantly increased (P0.05). After transfection of siRNA-NF- kappa B, the expression of NF- kappa B expression in the cells in the siRNA-NF-KB transfected group was significantly inhibited (P0.0) was significantly inhibited (P0.0) (P0.0) was significantly inhibited (P0.0) in the transfected group (P0.0). 5) but there was no change in the expression of C9orf72 protein. The MDA content in the normal group, the empty body group, the pcDNA3.1 (+) - (GGGGCC) 30 transfection group and the siRNA-NF- kappa B transfection group were (1.72 + 0.22) nmol/mgprot, (1.86 + 0.37) nmol/mgprot, (3.12 + 0.28) nmol/mgprot, (1.75 + 0.18) nmol/mgprot. statistical analysis showed pcDNA3.1 (+) - (+) - (+) - (+) - (+) - (+) - (+) - (+) - (+) - (+) - (+) - ATCACCATCACCAT (GGGGCC) 30 transfected group was significantly higher than that of other three groups (P0.05), and the MDA content in siRNA-NF-KB transfected group was not significantly different from that of the normal group and the empty carrier group (P0.05). Conclusion: This study successfully constructed the GGGGCC pair of C9orf72 induced ALS cell model.C9orf72 gene for 30 repetitions in the C9orf72 induced.C9orf72 gene. The cytotoxicity of.C9orf72 cells was observed, and the damage of neurons was induced by the downstream NF- kappa B signaling pathway.
【學(xué)位授予單位】：山東大學(xué)
【學(xué)位級別】：博士
【學(xué)位授予年份】：2017
【分類號】：R744.8

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