【摘要】：研究背景:高原地區(qū)以低氧、低氣壓、寒冷、相對濕度低和太陽輻射強為主要特征,其中對人類生命活動影響最為顯著的主要是低氧因素。人體暴露于高原低氧環(huán)境后,機體會從整體水平調(diào)動其內(nèi)在機制發(fā)生一系列的代償適應(yīng)性變化以應(yīng)對高原低氧環(huán)境,使機體內(nèi)環(huán)境由不平衡到平衡,最終達(dá)到內(nèi)、外環(huán)境的統(tǒng)一,這一過程稱為高原習(xí)服。機體對高原環(huán)境的習(xí)服是一個時間依賴的漸進(jìn)過程,在高原低氧暴露的不同時間階段,機體習(xí)服的優(yōu)勢反應(yīng)不同,表明不同習(xí)服階段的內(nèi)在機制及其分子基礎(chǔ)可能不同。多數(shù)人可通過習(xí)服獲得對高原環(huán)境良好的適應(yīng),但也有部分人因?qū)Ω咴h(huán)境的習(xí)服不良而發(fā)生各種急、慢性高原病。急性高原病包括急性高山病(acute mountain sickness,AMS)、高原肺水腫和高原腦水腫,其中AMS是快速進(jìn)入高原人群中最常見的疾病,未采取預(yù)防措施的急進(jìn)高原人群AMS發(fā)病率中位值高達(dá)60%。AMS患者常常喪失正常的作業(yè)能力,重度AMS患者如未及時治療,極易發(fā)展為高原腦水腫,直接威脅患者的生命。AMS已成為急進(jìn)高原人群生命健康的主要威脅。慢性高原病包括高原紅細(xì)胞增多癥(high altitude polycythemia,HAPC)和高原肺動脈高壓,其中HAPC是常駐高原人群中最為多見的慢性高原病,以紅細(xì)胞過度增生、血紅蛋白濃度顯著增加為主要特征,由于紅細(xì)胞過度增多導(dǎo)致血液粘滯度增高、微循環(huán)障礙,進(jìn)一步加重組織缺氧,患者易出現(xiàn)全身多個器官、系統(tǒng)損傷和血栓等嚴(yán)重并發(fā)癥。嚴(yán)重影響患者健康和生命安全。久居高原者返回平原后,隨著低氧刺激的消失,機體為適應(yīng)高原環(huán)境而發(fā)生的一系列功能、代謝和形態(tài)學(xué)方面的改變又要重新調(diào)整,以適應(yīng)平原環(huán)境,這一過程稱為脫習(xí)服。在此過程中,部分個體可表現(xiàn)出嗜睡、反應(yīng)力和記憶力減退等一系列臨床癥狀。有關(guān)高原習(xí)服及習(xí)服不良(高原病)的機制歷來是高原醫(yī)學(xué)關(guān)注的重點,雖然以往從生理、生化和形態(tài)學(xué)角度對高原習(xí)服進(jìn)行了大量研究,豐富了人們對高原習(xí)服的認(rèn)識,但迄今高原習(xí)服的分子機制尚不十分清楚并缺乏系統(tǒng)性的研究。有關(guān)AMS和HAPC發(fā)病機制的前期研究表明,AMS和HAPC的發(fā)生是眾多基因以及基因與高原低氧環(huán)境相互作用的結(jié)果,因此需要從系統(tǒng)的角度出發(fā)對其發(fā)生發(fā)展和運轉(zhuǎn)機制進(jìn)行研究�；虮磉_(dá)變化是轉(zhuǎn)錄組學(xué)研究的核心內(nèi)容,細(xì)胞轉(zhuǎn)錄組具有時空特異性,隨時間和空間的改變而改變,因此基因表達(dá)變化是細(xì)胞維持穩(wěn)態(tài)和改變自身狀態(tài)的主要途徑。對基因表達(dá)進(jìn)行分析是研究復(fù)雜表型分子機制的重要研究手段,且轉(zhuǎn)錄組學(xué)產(chǎn)生的富含大量生物學(xué)信息的基因表達(dá)數(shù)據(jù)為系統(tǒng)性的研究復(fù)雜表型的分子基礎(chǔ)提供了可能。因此本文圍繞“高原習(xí)服及習(xí)服不良過程中基因表達(dá)特征及其病理生理學(xué)意義”這一主題,從兩個部分詳細(xì)開展研究。第一部分,對漢族人群進(jìn)入高原前、進(jìn)入高原早期、中期、后期以及返回平原早期和后期進(jìn)行了連續(xù)動態(tài)的觀察。在此期間,采集個體生理數(shù)據(jù)及臨床癥狀表型,使用RNA-Seq技術(shù)檢測全血細(xì)胞基因表達(dá)情況,采用WGCNA算法尋找各時間階段特異表達(dá)基因,結(jié)合基因注釋數(shù)據(jù)庫以及文獻(xiàn)對其病理生理學(xué)意義進(jìn)行研究,深入了解高原習(xí)服的本質(zhì)。第二部分,比較AMS和HAPC患者與未患病者高原低氧暴露后基因表達(dá)變化,構(gòu)建并比較AMS和HAPC患者和未患病者差異表達(dá)基因共表達(dá)網(wǎng)絡(luò),從網(wǎng)絡(luò)水平研究與AMS和HAPC發(fā)生相關(guān)的基因共表達(dá)模式及其關(guān)鍵基因,為高原病發(fā)病機制的研究提供重要的線索。方法:1.本研究分別進(jìn)行了2次獨立的人群實驗:(1)動態(tài)觀察16名健康男性漢族志愿者人群進(jìn)入高原前、進(jìn)入高原(5300m)早期(3d)、中期(4m)、后期(1y)以及返回平原早期(1m)和后期(6m)血壓、心率及血氧飽和度變化,同時采集靜脈血用于RNA-Seq測序、血紅蛋白濃度檢測以及血漿細(xì)胞因子檢測;(2)采集109名健康男性漢族志愿者進(jìn)入高原前的靜脈血,分離血漿用于microRNA表達(dá)譜測定,觀察記錄志愿者進(jìn)入高原(3658m)后AMS的發(fā)病情況及癥狀評分。2.提取全血細(xì)胞總RNA,構(gòu)建PE測序文庫,采用Illumina HiSeq 2000測序平臺進(jìn)行RNA-Seq測序。3.采用BGI標(biāo)準(zhǔn)數(shù)據(jù)處理流程評估RNA-Seq原始序列數(shù)據(jù)質(zhì)量并比對到人類參考基因組(hg19);采用FPKM值對基因表達(dá)值進(jìn)行標(biāo)準(zhǔn)化和定量,R軟件包edgeR分析組間差異表達(dá)基因,取|Fold change|≥2且FDR≤0.05為閾值;采用WGCNA算法對基因表達(dá)量進(jìn)行系統(tǒng)分析,根據(jù)基因表達(dá)相似性劃分基因模塊,獲取進(jìn)入高原早期、中期、后期以及返回平原早期及后期特異表達(dá)基因并根據(jù)基因間關(guān)聯(lián)度構(gòu)建各自共表達(dá)網(wǎng)絡(luò);使用clusterProfiler軟件包及在線分析工具REVIGO對各階段特異表達(dá)基因進(jìn)行生物學(xué)注釋;結(jié)合已報道文獻(xiàn)對網(wǎng)絡(luò)中關(guān)鍵基因的生物學(xué)功能進(jìn)行詳細(xì)探討。4.使用RPKM標(biāo)準(zhǔn)化和定量AMS患者與未患病者轉(zhuǎn)錄本表達(dá)量;采用density based pruning算法篩選AMS患者和未患病者急進(jìn)高原前后差異表達(dá)轉(zhuǎn)錄本;使用DAVID中Gene Functional Classification工具對差異表達(dá)轉(zhuǎn)錄本進(jìn)行生物學(xué)注釋并歸類;根據(jù)聚類網(wǎng)絡(luò)理論計算AMS患者與未發(fā)病者進(jìn)入高原后基因的拓?fù)渲睾暇仃嘜T(i,j),并構(gòu)建比較兩者基因共表達(dá)網(wǎng)絡(luò)的拓?fù)浣Y(jié)構(gòu)。5.使用ELISA法對AMS患者和未患病者血漿中IL10、CCL8及IL17F含量進(jìn)行檢測;采用化學(xué)發(fā)光法對AMS患者和未患病者IL10含量進(jìn)行重復(fù)性驗證。6.使用miRCURYTM LNA Array檢測健康男性漢族志愿者進(jìn)入高原前血漿中microRNA表達(dá)譜;使用qRT-PCR法對差異microRNA進(jìn)行驗證并使用R軟件包OptimalCutpoints對其在AMS發(fā)病風(fēng)險中的預(yù)測效能進(jìn)行評價。7.使用microT-CDS和TarBase工具對microRNA的調(diào)控靶基因進(jìn)行分析;使用DIANA-miRPath對microRNA靶基因進(jìn)行生物學(xué)注釋。8.采用FPKM對HAPC患者和未發(fā)病者基因表達(dá)標(biāo)準(zhǔn)化和定量,R軟件包egdeR分析組間差異表達(dá)基因,取|Fold change|≥2且FDR≤0.05為閾值;使用clusterProfiler軟件包及在線分析工具REVIGO對HAPC患者和未發(fā)病者關(guān)聯(lián)基因進(jìn)行生物學(xué)注釋;采用斯皮爾曼相關(guān)系數(shù)法構(gòu)建HAPC患者和未患病者進(jìn)入高原后差異上調(diào)基因共表達(dá)網(wǎng)絡(luò);采用Concentric對HAPC患者和未患病者基因共表達(dá)網(wǎng)絡(luò)進(jìn)行比較,明確HAPC發(fā)生相關(guān)的基因共表達(dá)模式及關(guān)鍵基因。結(jié)果:1.進(jìn)入高原早期,參與多巴胺代謝、離子轉(zhuǎn)運及血紅蛋白合成的基因特異性表達(dá),基因MXI1、RNF10、TRIM58、GLRX5和BPGM處于共表達(dá)網(wǎng)絡(luò)的中心位置;中期,基因表達(dá)模式與進(jìn)入高原前相似;后期,參與磷代謝、免疫系統(tǒng)與MAPK信號通路調(diào)節(jié)、細(xì)胞內(nèi)吞及囊泡轉(zhuǎn)運的基因特異性表達(dá),基因SMARCD2、CDK9及RIC8A處于共表達(dá)網(wǎng)絡(luò)的中心位置。2.返回平原早期,參與大分子物質(zhì)、核酸代謝,細(xì)胞增殖分化的基因特異性表達(dá),基因MTF2、ZFR、CAND1、DEPDC1、DEPDC1B、CCNA2、CDC6、CDC20、CCNB2、CCNB1和ANLN處于共表達(dá)網(wǎng)絡(luò)的中心位置;后期參與免疫炎癥反應(yīng)的基因特異性表達(dá),基因ZBP1、STAT2、IFIT1、IFIT2和IFIT3處于共表達(dá)網(wǎng)絡(luò)的中心位置。3.與AMS未發(fā)病者相比,免疫和炎癥反應(yīng)在AMS患者差異表達(dá)轉(zhuǎn)錄本中顯著富集(富集分?jǐn)?shù):3.44,3.27);AMS患者與未患病者基因共表達(dá)網(wǎng)絡(luò)中IL10、CCL8和IL17F的度存在顯著差異;蛋白水平上,進(jìn)入高原后AMS患者IL10的表達(dá)顯著下調(diào),CCL8和IL17F顯著增加,未發(fā)病者IL10顯著上調(diào),IL17F顯著下調(diào),CCL8改變無統(tǒng)計學(xué)差異;且在另一人群中,急進(jìn)高原后,AMS患者IL10蛋白顯著下調(diào)(p=0.001),未患病者無顯著改變,IL10的改變量與急進(jìn)高原個體臨床癥狀評分間存在較強的相關(guān)性,r(22)=-0.52,p=0.013。4.進(jìn)入高原前,AMS患者血漿miR-369-3p、miR-449b-3p和miR-136-3p表達(dá)量顯著高于未患病者;采用Logistic回歸模型發(fā)現(xiàn)miR-369-3p、miR-449b-3p和miR-136-3p組合對AMS發(fā)病風(fēng)險預(yù)測的敏感度和特異度達(dá)到92.68%和93.48%,AUC:0.986,95%CI:0.970-1.000,p0.001,LR+:14.21,LR-:0.08;生物信息學(xué)分析提示miR-369-3p,mi R-449b-3p和mi R-136-3p調(diào)控的靶基因主要參與含氮化合物的代謝過程及神經(jīng)營養(yǎng)因子TRK受體信號通路。5.HAPC患者較未發(fā)病者具有311個特有的差異上調(diào)基因,顯著富集于細(xì)胞增殖以及免疫調(diào)控過程;進(jìn)入高原后,HAPC患者表達(dá)上調(diào)基因共表達(dá)網(wǎng)絡(luò)平均度為22.64,是未患病者的2倍(11.85);HAPC患者差異上調(diào)基因共表達(dá)網(wǎng)絡(luò)中,中心性(Betweeness centrality)較高的基因為IFT20和MRPL22,分別為0.50和0.46,未患病者中,中心性較高的基因為ITGAV和TPRKB,分別為0.50和0.37。結(jié)論:1.進(jìn)入高原早期,機體以MXI1、RNF10、TRIM58、GLRX5及BPGM為核心表達(dá)基因,調(diào)控參與多巴胺代謝、離子轉(zhuǎn)運及血紅蛋白合成基因,提示在高原習(xí)服早期,機體主要通過增加氧氣攝入、運輸以及氧合血紅蛋白氧釋放效率等適應(yīng)高原環(huán)境,以實現(xiàn)機體內(nèi)、外環(huán)境的基本平衡;隨著高原暴露時間的延長,機體調(diào)動更多內(nèi)在機制參與內(nèi)環(huán)境穩(wěn)態(tài)的調(diào)節(jié),其中以SMARCD2、CDK9及RIC8A為核心表達(dá)基因。這些基因通過調(diào)控參與磷代謝、免疫系統(tǒng)與MAPK信號通路調(diào)節(jié)、細(xì)胞內(nèi)吞及囊泡轉(zhuǎn)運的基因,促進(jìn)紅細(xì)胞增殖增加氧的運輸,促進(jìn)組織血管新生縮短氧的彌散距離以及增強組織細(xì)胞對氧的利用等多種機制習(xí)服高原環(huán)境。在此過程中,機體的免疫系統(tǒng)激活,其意義可能在于防御低氧損傷,確保機體自身穩(wěn)定。2.從高原返回平原早期,機體以MTF2、DEPDC1、DEPDC1B、CCNA2、CDC6、CDC20、CCNB2、CCNB1和ANLN為核心表達(dá)基因,通過調(diào)控細(xì)胞的增殖分化,建立內(nèi)環(huán)境平衡狀態(tài);后期以ZBP1、STAT2及IFIT家族為核心表達(dá)基因,參與并增強免疫炎癥反應(yīng),清除內(nèi)源性損傷因子并修復(fù)損傷組織。3.炎癥反應(yīng)增強是AMS發(fā)生的重要機制。高原低氧引起AMS患者基因共表達(dá)模式改變,導(dǎo)致抗炎因子IL10分泌減少,促炎細(xì)胞因子CCL8和IL17F分泌增加,可能是促使炎癥反應(yīng)增強進(jìn)而發(fā)生AMS的重要機制。4.漢族人進(jìn)入高原前的血漿microRNA水平與AMS的發(fā)病風(fēng)險密切相關(guān),其中血漿miR-369-3p、miR-449b-3p和miR-136-3p分子組合對AMS的發(fā)病風(fēng)險具有很好的預(yù)測效能,提示其是一種新的預(yù)測AMS易感性的生物標(biāo)志物。5.參與細(xì)胞增殖以及免疫反應(yīng)的基因過度上調(diào)以及基因間特有的共表達(dá)關(guān)系與HAPC的發(fā)生密切相關(guān),其中以IFT20和MRPL22的作用尤為關(guān)鍵,提示其可能是HAPC發(fā)病的重要環(huán)節(jié)和防治的重要靶點。綜上所述,本論文采用RNA-Seq技術(shù)首次對漢族人群進(jìn)入高原前,進(jìn)入高原早期、中期和后期以及返回平原早期和后期全過程全血細(xì)胞基因表達(dá)進(jìn)行了動態(tài)觀察,從系統(tǒng)的角度對高原習(xí)服及脫習(xí)服過程中不同時間段特異表達(dá)基因及其病理生理學(xué)意義進(jìn)行了研究,為理解高原習(xí)服的本質(zhì)提供了重要的理論依據(jù)。從整體水平對AMS和HAPC患者與未患病者的基因表達(dá)進(jìn)行了分析比較,發(fā)現(xiàn)了與AMS和HAPC發(fā)病相關(guān)的基因共表達(dá)模式及其關(guān)鍵基因,為今后深入研究AMS和HAPC提供了重要的線索。同時,首次報導(dǎo)了循環(huán)microRNA分子在AMS的發(fā)病風(fēng)險預(yù)測中的作用,發(fā)現(xiàn)了可用于AMS預(yù)防的全新的生物標(biāo)志物。
[Abstract]:BACKGROUND: The plateau area is characterized by hypoxia, low pressure, cold, low relative humidity and strong solar radiation. The most significant factors affecting human life activities are hypoxia. High altitude acclimatization is a time-dependent gradual process in which the body acclimatizes to the high altitude hypoxic environment. At different stages of altitude hypoxic exposure, the body acclimatizes to different advantages, indicating different acclimatization stages. The underlying mechanism and molecular basis may be different. Most people can acquire a good adaptation to the high altitude environment by acclimation, but some people develop various acute and chronic high altitude diseases due to poor acclimation to the high altitude environment. Acute high altitude diseases include acute mountain sickness (AMS), high altitude pulmonary edema and high altitude brain edema, including AMS. AMS is the most common disease among people who enter the plateau rapidly. The median incidence of AMS is as high as 60% among people who enter the plateau rapidly without preventive measures. AMS patients often lose their normal working ability. If severe AMS patients are not treated in time, they will easily develop into high altitude brain edema, which directly threatens the lives of patients. AMS has become a healthy life for people who enter the plateau rapidly. Chronic plateau diseases include high altitude polycythemia (HAPC) and high altitude pulmonary hypertension, of which HAPC is the most common chronic plateau disease in people living at high altitudes, characterized by excessive erythrocyte hyperplasia and marked increase in hemoglobin concentration, resulting in excessive red blood cell hyperplasia leading to blood pressure. High viscosity, microcirculation disturbance, and further aggravation of tissue hypoxia, patients are prone to multiple organs of the body, system damage and thrombosis and other serious complications, seriously affecting the health and safety of patients. Morphological changes have to be readjusted to fit the plain environment, a process known as acclimatization, in which some individuals exhibit a range of clinical symptoms such as drowsiness, loss of responsiveness and memory. Physiological, biochemical and morphological studies on altitude acclimatization have enriched people's understanding of altitude acclimatization, but the molecular mechanism of altitude acclimatization is still unclear and lack of systematic research.Previous studies on the pathogenesis of AMS and HAPC have shown that the occurrence of AMS and HAPC is a large number of genes, as well as genes and altitude lows. Gene expression changes are the core of transcriptome research. Cell transcriptome is space-time specific and changes with time and space. Therefore, gene expression changes are the maintenance of homeostasis and self-change of cells. The analysis of gene expression is an important means to study the molecular mechanism of complex phenotypes, and the data of gene expression rich in biological information produced by transcriptome provide a possibility for the systematic study of the molecular basis of complex phenotypes. In the first part, a continuous dynamic observation was carried out on the Han population before entering the plateau, early, middle, late, and early and late return to the plain. RNA-Seq technique was used to detect gene expression in whole blood cells, and WGCNA algorithm was used to find the specific expression genes at different time stages. The pathophysiological significance of gene annotation database and literature were studied to understand the essence of altitude acclimation. Part 2: Comparing AMS and HAPC patients with and without altitude hypoxia exposure. The co-expression patterns and key genes related to the occurrence of AMS and HAPC were studied from the network level, providing important clues for the study of the pathogenesis of altitude sickness. Methods: 1. Two independent population studies were conducted. The results were as follows: (1) Blood pressure, heart rate and oxygen saturation were dynamically observed in 16 healthy male Han volunteers before entering the plateau, at the early (3d), middle (4m), late (1y) and early (1m) and late (6m) after returning to the plateau, and venous blood was collected for RNA-Seq sequencing, hemoglobin concentration detection and plasma cytokines detection. (2) Blood samples were collected from 109 healthy male Han volunteers before they entered the plateau. Plasma samples were separated for microRNA expression profiling. The incidence and symptom score of AMS were observed and recorded after they entered the plateau (3658m). Total RNA of whole blood cells was extracted and the PE sequencing library was constructed. RNA-Seq was sequenced by Illumina HiSeq 2000. The quality of original RNA-Seq sequence data was assessed by BGI standard data processing flow and compared with human reference genome (hg19); the gene expression values were standardized and quantified by FPKM value; the differentially expressed genes between groups were analyzed by R software package edgeR, and the | Fold change | 2 and FDR | 0.05 were taken as thresholds; the gene expression was systematically analyzed by WGCNA algorithm. According to the similarity of gene expression, we divided the gene modules into early, middle, late and return to the plain, and constructed their co-expression networks according to the degree of gene association; using cluster Profiler software package and on-line analysis tool REVIGO to biologically analyze the stage-specific genes. Notes: Biological functions of key genes in the network were discussed in detail with the reported literature. 4. RPKM was used to standardize and quantify the transcripts of AMS patients and non-AMS patients; density-based pruning algorithm was used to screen differentially expressed transcripts of AMS patients and non-AMS patients before and after acute plateau entry; and Gene Functional Clas in DAVID was used. The sification tool was used to annotate and classify the differentially expressed transcripts; the topological coincidence matrix OT (i, j) of AMS patients and non-AMS patients was calculated according to clustering network theory, and the topological structure of the gene co-expression network was constructed and compared. 5. The plasma IL 10, CCL8 and IL in AMS patients and non-AMS patients were analyzed by ELISA. Serum microRNA expression profiles of healthy male Han volunteers before entering the plateau were detected by using microRNAs microRNA expression profiles; differentially expressed microRNAs were validated by qRT-PCR and were detected by R software package Optimal Cutpoints in AMS. Evaluation of predictive efficacy in disease risk. 7. MicroRNA regulatory target genes were analyzed using microT-CDS and TarBase tools; microRNA target genes were biologically annotated using DIANA-MicroPath. Old change | 2 and FDR < 0.05 were used as thresholds; the association genes between HAPC patients and non-HAPC patients were biologically annotated by cluster Profiler software package and on-line analysis tool REVIGO; the co-expression networks of differentially up-regulated genes between HAPC patients and non-HAPC patients were constructed by Spearman correlation coefficient method; and the concentric was used for HAPC patients. Results: 1. In the early stage of Plateau entry, genes involved in dopamine metabolism, ion transport and hemoglobin synthesis were specifically expressed. Genes MXI1, RNF10, TRIM58, GLRX5 and BPGM were at the center of the co-expression network. The gene expression pattern was similar to that before entering the plateau; at the later stage, the genes involved in phosphorus metabolism, immune system and MAPK signaling pathway, endocytosis and vesicle transport were specifically expressed, and SMARCD2, CDK9 and RIC8A were at the center of the co-expression network. 2. Back to the early plain, the genes involved in macromolecular substances, nucleic acid metabolism, cell proliferation and differentiation. Because of specific expression, genes MTF2, ZFR, CAND1, DEPDC1, DEPDC1B, CCNA2, CDC6, CDC20, CCNB2, CCNB1 and ANLN are at the center of the co-expression network; genes ZBP1, STAT2, IFIT1, IFIT2 and IFIT3 are at the center of the co-expression network in the late stage of immune inflammation, compared with those without AMS. The response was significantly enriched in the differentially expressed transcripts of AMS patients (enrichment fraction: 3.44, 3.27); the degree of IL 10, CCL8 and IL 17F in the gene co-expression network of AMS patients and non-AMS patients was significantly different; at protein level, the expression of IL 10 in AMS patients was significantly down-regulated, CCL8 and IL 17F were significantly increased, IL 10 was significantly up-regulated in non-AMS patients, and IL 17F was significantly up-regulated in AMS patients at high altitude. There was no significant difference in CCL8, and in another group, IL-10 protein was significantly decreased in AMS patients (p = 0.001) after acute high altitude entry, and no significant change was found in non-AMS patients. There was a strong correlation between the change of IL-10 and the individual clinical symptom score of acute high altitude entry, R (22) = - 0.52, P = 0.013.4. The expression levels of 9b-3p and microwave-136-3p were significantly higher than those of non-patients; Logistic regression model showed that the sensitivity and specificity of the combination of microwave-369-3p, microwave-449b-3p and microwave-136-3p to the risk prediction of AMS were 92.68% and 93.48%, AUC: 0.986, 95% CI: 0.970-1.000, p0.001, LR +: 14.21, LR - - 0.08; Bioinformatics analysis indicated that the combination of microwave-369-3p, microwave-449-3b, and microwave-449b-3p was sensitive and specific to the risk prediction of AMS. The target genes regulated by MIR-136-3p and MIR-136-3p are mainly involved in the metabolic process of nitrogen compounds and the signaling pathway of neurotrophic factor TRK receptor. The mean value was 22.64, twice as high as that of non-HAPC patients (11.85). In the co-expression network of differentially up-regulated genes in HAPC patients, the genes with higher centrality were IFT2 0 and MRPL22, respectively, 0.50 and 0.46. In non-HAPC patients, the genes with higher centrality were ITGAV and TPRKB, respectively, 0.50 and 0.37. Conclusion: 1. In the early stage of Plateau entry, the organisms with MXI1, R, and TPRKB had higher centrality. NF10, TRIM58, GLRX5 and BPGM are the core expression genes, which regulate dopamine metabolism, ion transport and hemoglobin synthesis. It is suggested that in the early stage of altitude acclimation, the organism adapts to altitude environment mainly by increasing oxygen intake, transport and oxygen release efficiency of oxyhemoglobin, so as to achieve the basic balance between the internal and external environment. With prolonged exposure time, the body mobilizes more internal mechanisms to participate in the regulation of homeostasis of the internal environment, in which SMARCD2, CDK9 and RIC8A are the core expression genes. These genes are involved in phosphorus metabolism, immune system and MAPK signal pathway regulation, endocytosis and vesicle transport genes, promote red blood cell proliferation and oxygen transport, promote Tissue angiogenesis shortens the diffusion distance of oxygen and enhances the utilization of oxygen by tissue cells. During this process, the immune system is activated, which may be of significance in preventing hypoxic injury and ensuring the stability of the body. 2. In the early stage of returning to the plain from the plateau, the body uses MTF2, DEPDC1, DEPDC1B, CCNA2, CDC6, CDC20. CCNB2, CCNB1 and ANLN are the core expression genes, which regulate cell proliferation and differentiation to establish internal environment balance; ZBP1, STAT2 and IFIT family are the core expression genes in the late stage, participate in and enhance immune inflammation, remove endogenous injury factors and repair damaged tissues. 3. Increased inflammation is an important mechanism of AMS. Oxygen induces alterations in gene co-expression patterns in AMS patients, resulting in decreased secretion of anti-inflammatory factors IL10 and increased secretion of pro-inflammatory cytokines CCL8 and IL17F.
【學(xué)位授予單位】：第三軍醫(yī)大學(xué)
【學(xué)位級別】：博士
【學(xué)位授予年份】：2017
【分類號】：R594.3

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