【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性變化以應對高原低氧環(huán)境,使機體內(nèi)環(huán)境由不平衡到平衡,最終達到內(nèi)、外環(huán)境的統(tǒng)一,這一過程稱為高原習服。機體對高原環(huán)境的習服是一個時間依賴的漸進過程,在高原低氧暴露的不同時間階段,機體習服的優(yōu)勢反應不同,表明不同習服階段的內(nèi)在機制及其分子基礎可能不同。多數(shù)人可通過習服獲得對高原環(huán)境良好的適應,但也有部分人因?qū)Ω咴h(huán)境的習服不良而發(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是快速進入高原人群中最常見的疾病,未采取預防措施的急進高原人群AMS發(fā)病率中位值高達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已成為急進高原人群生命健康的主要威脅。慢性高原病包括高原紅細胞增多癥(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,以紅細胞過度增生、血紅蛋白濃度顯著增加為主要特征,由于紅細胞過度增多導致血液粘滯度增高、微循環(huán)障礙,進一步加重組織缺氧,患者易出現(xiàn)全身多個器官、系統(tǒng)損傷和血栓等嚴重并發(fā)癥。嚴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,機體為適應高原環(huán)境而發(fā)生的一系列功能、代謝和形態(tài)學方面的改變又要重新調(diào)整,以適應平原環(huán)境,這一過程稱為脫習服。在此過程中,部分個體可表現(xiàn)出嗜睡、反應力和記憶力減退等一系列臨床癥狀。有關(guān)高原習服及習服不良(高原病)的機制歷來是高原醫(yī)學關(guān)注的重點,雖然以往從生理、生化和形態(tài)學角度對高原習服進行了大量研究,豐富了人們對高原習服的認識,但迄今高原習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)機制進行研究�；虮磉_變化是轉(zhuǎn)錄組學研究的核心內(nèi)容,細胞轉(zhuǎn)錄組具有時空特異性,隨時間和空間的改變而改變,因此基因表達變化是細胞維持穩(wěn)態(tài)和改變自身狀態(tài)的主要途徑。對基因表達進行分析是研究復雜表型分子機制的重要研究手段,且轉(zhuǎn)錄組學產(chǎn)生的富含大量生物學信息的基因表達數(shù)據(jù)為系統(tǒng)性的研究復雜表型的分子基礎提供了可能。因此本文圍繞“高原習服及習服不良過程中基因表達特征及其病理生理學意義”這一主題,從兩個部分詳細開展研究。第一部分,對漢族人群進入高原前、進入高原早期、中期、后期以及返回平原早期和后期進行了連續(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)檢測全血細胞基因表達情況,采用WGCNA算法尋找各時間階段特異表達基因,結(jié)合基因注釋數(shù)據(jù)庫以及文獻對其病理生理學意義進行研究,深入了解高原習服的本質(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變化,構(gòu)建并比較AMS和HAPC患者和未患病者差異表達基因共表達網(wǎng)絡,從網(wǎng)絡水平研究與AMS和HAPC發(fā)生相關(guān)的基因共表達模式及其關(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入高原前、進入高原(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胞因子檢測;(2)采集109名健康男性漢族志愿者進入高原前的靜脈血,分離血漿用于microRNA表達譜測定,觀察記錄志愿者進入高原(3658m)后AMS的發(fā)病情況及癥狀評分。2.提取全血細胞總RNA,構(gòu)建PE測序文庫,采用Illumina HiSeq 2000測序平臺進行RNA-Seq測序。3.采用BGI標準數(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值對基因表達值進行標準化和定量,R軟件包edgeR分析組間差異表達基因,取|Fold change|≥2且FDR≤0.05為閾值;采用WGCNA算法對基因表達量進行系統(tǒng)分析,根據(jù)基因表達相似性劃分基因模塊,獲取進入高原早期、中期、后期以及返回平原早期及后期特異表達基因并根據(jù)基因間關(guān)聯(lián)度構(gòu)建各自共表達網(wǎng)絡;使用clusterProfiler軟件包及在線分析工具REVIGO對各階段特異表達基因進行生物學注釋;結(jié)合已報道文獻對網(wǎng)絡中關(guān)鍵基因的生物學功能進行詳細探討。4.使用RPKM標準化和定量AMS患者與未患病者轉(zhuǎn)錄本表達量;采用density based pruning算法篩選AMS患者和未患病者急進高原前后差異表達轉(zhuǎn)錄本;使用DAVID中Gene Functional Classification工具對差異表達轉(zhuǎn)錄本進行生物學注釋并歸類;根據(jù)聚類網(wǎng)絡理論計算AMS患者與未發(fā)病者進入高原后基因的拓撲重合矩陣OT(i,j),并構(gòu)建比較兩者基因共表達網(wǎng)絡的拓撲結(jié)構(gòu)。5.使用ELISA法對AMS患者和未患病者血漿中IL10、CCL8及IL17F含量進行檢測;采用化學發(fā)光法對AMS患者和未患病者IL10含量進行重復性驗證。6.使用miRCURYTM LNA Array檢測健康男性漢族志愿者進入高原前血漿中microRNA表達譜;使用qRT-PCR法對差異microRNA進行驗證并使用R軟件包OptimalCutpoints對其在AMS發(fā)病風險中的預測效能進行評價。7.使用microT-CDS和TarBase工具對microRNA的調(diào)控靶基因進行分析;使用DIANA-miRPath對microRNA靶基因進行生物學注釋。8.采用FPKM對HAPC患者和未發(fā)病者基因表達標準化和定量,R軟件包egdeR分析組間差異表達基因,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)基因進行生物學注釋;采用斯皮爾曼相關(guān)系數(shù)法構(gòu)建HAPC患者和未患病者進入高原后差異上調(diào)基因共表達網(wǎng)絡;采用Concentric對HAPC患者和未患病者基因共表達網(wǎng)絡進行比較,明確HAPC發(fā)生相關(guān)的基因共表達模式及關(guān)鍵基因。結(jié)果:1.進入高原早期,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,基因MXI1、RNF10、TRIM58、GLRX5和BPGM處于共表達網(wǎng)絡的中心位置;中期,基因表達模式與進入高原前相似;后期,參與磷代謝、免疫系統(tǒng)與MAPK信號通路調(diào)節(jié)、細胞內(nèi)吞及囊泡轉(zhuǎn)運的基因特異性表達,基因SMARCD2、CDK9及RIC8A處于共表達網(wǎng)絡的中心位置。2.返回平原早期,參與大分子物質(zhì)、核酸代謝,細胞增殖分化的基因特異性表達,基因MTF2、ZFR、CAND1、DEPDC1、DEPDC1B、CCNA2、CDC6、CDC20、CCNB2、CCNB1和ANLN處于共表達網(wǎng)絡的中心位置;后期參與免疫炎癥反應的基因特異性表達,基因ZBP1、STAT2、IFIT1、IFIT2和IFIT3處于共表達網(wǎng)絡的中心位置。3.與AMS未發(fā)病者相比,免疫和炎癥反應在AMS患者差異表達轉(zhuǎn)錄本中顯著富集(富集分數(shù):3.44,3.27);AMS患者與未患病者基因共表達網(wǎng)絡中IL10、CCL8和IL17F的度存在顯著差異;蛋白水平上,進入高原后AMS患者IL10的表達顯著下調(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)計學差異;且在另一人群中,急進高原后,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.進入高原前,AMS患者血漿miR-369-3p、miR-449b-3p和miR-136-3p表達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)病風險預測的敏感度和特異度達到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,顯著富集于細胞增殖以及免疫調(diào)控過程;進入高原后,HAPC患者表達上調(diào)基因共表達網(wǎng)絡平均度為22.64,是未患病者的2倍(11.85);HAPC患者差異上調(diào)基因共表達網(wǎng)絡中,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.進入高原早期,機體以MXI1、RNF10、TRIM58、GLRX5及BPGM為核心表達基因,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)、細胞內(nèi)吞及囊泡轉(zhuǎn)運的基因,促進紅細胞增殖增加氧的運輸,促進組織血管新生縮短氧的彌散距離以及增強組織細胞對氧的利用等多種機制習服高原環(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為核心表達基因,通過調(diào)控細胞的增殖分化,建立內(nèi)環(huán)境平衡狀態(tài);后期以ZBP1、STAT2及IFIT家族為核心表達基因,參與并增強免疫炎癥反應,清除內(nèi)源性損傷因子并修復損傷組織。3.炎癥反應增強是AMS發(fā)生的重要機制。高原低氧引起AMS患者基因共表達模式改變,導致抗炎因子IL10分泌減少,促炎細胞因子CCL8和IL17F分泌增加,可能是促使炎癥反應增強進而發(fā)生AMS的重要機制。4.漢族人進入高原前的血漿microRNA水平與AMS的發(fā)病風險密切相關(guān),其中血漿miR-369-3p、miR-449b-3p和miR-136-3p分子組合對AMS的發(fā)病風險具有很好的預測效能,提示其是一種新的預測AMS易感性的生物標志物。5.參與細胞增殖以及免疫反應的基因過度上調(diào)以及基因間特有的共表達關(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)首次對漢族人群進入高原前,進入高原早期、中期和后期以及返回平原早期和后期全過程全血細胞基因表達進行了動態(tài)觀察,從系統(tǒng)的角度對高原習服及脫習服過程中不同時間段特異表達基因及其病理生理學意義進行了研究,為理解高原習服的本質(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進行了分析比較,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,首次報導了循環(huán)microRNA分子在AMS的發(fā)病風險預測中的作用,發(fā)現(xiàn)了可用于AMS預防的全新的生物標志物。
[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.
【學位授予單位】：第三軍醫(yī)大學
【學位級別】：博士
【學位授予年份】：2017
【分類號】：R594.3

【相似文獻】

相關(guān)期刊論文 前10條

1 尹旭輝,于寧,陳秋紅,揚成君,揚義軍,姜在福;冷習服對機體氨基酸代謝的影響[J];中國公共衛(wèi)生;2000年12期

2 高鈺琪,羅德成,牛文忠,黃緘,黃慶愿,劉福玉;高原習服的評價標準與方法研究[J];第三軍醫(yī)大學學報;2001年12期

3 高鈺琪 ,王小珍;高原習服的評價標準與方法研究[J];高原醫(yī)學雜志;2002年01期

4 王小珍;促進高原習服措施的研究進展[J];高原醫(yī)學雜志;2003年01期

5 廖巨輪,于國書;習服時間與高原反應600例[J];鐵道建筑技術(shù);2003年S1期

6 羅勇軍;陳郁;蔣春華;周其全;高鈺琪;;健康青年男性乘火車快速進入高原后初步/基本習服情況[J];高原醫(yī)學雜志;2009年S1期

7 劉燕;趙群;王福領;劉福玉;羅勇軍;蔣春華;李瀟瀟;高鈺琪;;步兵摩托化進駐4300m高原半年內(nèi)習服狀況評價[J];第三軍醫(yī)大學學報;2011年09期

8 張華耀;張彥雪;楊哲新;黃們;王菲菲;孔繁玲;;習服高原與脫習服[J];中國應用生理學雜志;2012年01期

9 邱仞之,符振雄,王會民,胡德泉,萬為人;獼猴高效熱習服方法的研究[J];應用生理學雜志;1986年02期

10 謝濟三;;選擇高原習服型的人開拓高原[J];青海醫(yī)藥雜志;1986年06期

相關(guān)會議論文 前10條

1 黃tJ;高鈺琪;張國斌;羅德成;曹利飛;孫秉庸;;缺氧習服大鼠骨骼肌葡萄糖攝取能力貯備增強[A];第六次全國缺氧和呼吸病理生理學術(shù)會議論文摘要匯編[C];2003年

2 高鈺琪;孫秉庸;;高原缺氧習服的研究進展[A];第六次全國缺氧和呼吸病理生理學術(shù)會議論文摘要匯編[C];2003年

3 李立青;田亞平;董矜;張陽東;胡金川;溫新宇;;高通量測定基因表達方法的建立及運動相關(guān)基因表達的檢測[A];第七屆全國醫(yī)學生物化學與分子生物學和第四屆全國臨床應用生物化學與分子生物學聯(lián)合學術(shù)研討會暨醫(yī)學生化分會會員代表大會論文集[C];2011年

4 鄧大君;;基因表達群與中醫(yī)證概念的關(guān)系[A];中醫(yī)現(xiàn)代化科學研究發(fā)展策略[C];1999年

5 周天壽;;染色質(zhì)控制的隨機基因表達[A];第一屆全國神經(jīng)動力學學術(shù)會議程序手冊 & 論文摘要集[C];2012年

6 奚文輝;張文廣;李金泉;張燕軍;王敏;馮林;;單細胞PCR在哺乳動物毛囊基因表達研究中的應用[A];中國動物遺傳育種研究進展——第十五次全國動物遺傳育種學術(shù)討論會論文集[C];2009年

7 盧學春;朱宏麗;范輝;李素霞;姚善謙;;LRP16基因表達抑制劑的生物信息學篩查[A];第11次中國實驗血液學會議論文匯編[C];2007年

8 計峰;羅緒剛;李素芬;劉彬;余順祥;;鋅對基因表達的影響[A];中國營養(yǎng)學會第七屆微量元素營養(yǎng)學術(shù)會議論文摘要匯編[C];2001年

9 李擁軍;趙有璋;;哺乳動物早期胚胎發(fā)育的基因表達[A];中國畜牧獸醫(yī)學會養(yǎng)羊?qū)W分會全國養(yǎng)羊生產(chǎn)與學術(shù)研討會議論文集[C];2005年

10 張波;陳寶安;高沖;高峰;夏國華;邵澤葉;丁家華;趙剛;程堅;王駿;宋慧慧;鮑文;仲悅嬌;裴孝平;王飛;;骨髓增生異常綜合征相關(guān)基因表達研究[A];第12屆全國實驗血液學會議論文摘要[C];2009年

相關(guān)重要報紙文章 前10條

1 記者 賀鳳珊 通訊員 張寧;格爾木習服基地為工程建設提供良好醫(yī)療保障[N];格爾木日報;2010年

2 王嘉興;中秋冷習服 冬天少生病[N];醫(yī)藥養(yǎng)生保健報;2007年

3 廖巨輪;如何預防和減輕高原反應[N];中國鐵道建筑報;2003年

4 本報通訊員 水小瑩;階梯“攀登”高原 閱讀神奇青海[N];青海日報;2006年

5 吳楚;開山之作 特色鮮明[N];中國新聞出版報;2006年

6 記者 鐵錚 通訊員 李鑫;基因表達研究攻克世界性難題[N];中國綠色時報;2013年

7 常麗君;細胞內(nèi)的分子聚集有利于基因表達[N];科技日報;2013年

8 胡軒逸;環(huán)境影響基因表達[N];光明日報;2014年

9 蘇信;江蘇省基因表達工程研究中心成立[N];醫(yī)藥經(jīng)濟報;2001年

10 記者 劉鵬 通訊員 陳們;藏族人群基因表達具有地域性[N];光明日報;2014年

相關(guān)博士學位論文 前10條

1 劉寶;高原習服及習服不良過程中基因表達特征及其病理生理學意義研究[D];第三軍醫(yī)大學;2017年

2 毛孫忠;高原習服過程中骨骼肌脂肪氧化利用特點、機制及意義[D];第三軍醫(yī)大學;2008年

3 黃tJ;缺氧習服過程中組織葡萄糖攝取特點及其機制[D];第三軍醫(yī)大學;2003年

4 羅勇軍;線粒體基因組與高原習服適應相關(guān)性的初步研究[D];第三軍醫(yī)大學;2008年

5 倪倩;高原習服中大鼠肝臟葡萄糖、脂肪酸代謝特點及機制[D];蘭州大學;2014年

6 李利;綿羊胚胎發(fā)育后期骨骼肌中轉(zhuǎn)錄組水平基因表達分析及基因網(wǎng)絡的構(gòu)建[D];中國農(nóng)業(yè)科學院;2012年

7 Samuel Jerry Cobbina;[D];江蘇大學;2015年

8 周寧;鋅對水貂毛色基因表達及生產(chǎn)性能的影響[D];延邊大學;2015年

9 章琳;基于基因表達秩序關(guān)系識別癌癥預后與早期診斷標志[D];電子科技大學;2014年

10 丁艷芬;玉米ZmCPK11在ABA誘導的抗氧化防護中的功能分析[D];南京農(nóng)業(yè)大學;2012年

相關(guān)碩士學位論文 前10條

1 易均鳳;自噬溶酶體途徑在熱習服保護熱射病腦損傷中的作用[D];第三軍醫(yī)大學;2015年

2 卜苓南;認知行為—習服療法治療耳鳴的臨床研究[D];皖南醫(yī)學院;2015年

3 李玉祥;熱習服提高濕熱環(huán)境下大鼠線粒體適應性變化研究[D];上海體育學院;2016年

4 葉楠;熱習服上調(diào)Treg細胞減輕小鼠熱應激損傷的研究[D];第三軍醫(yī)大學;2016年

5 沈丹丹;高溫高濕環(huán)境下熱習服訓練及其效果影響因素的實驗研究[D];天津大學;2016年

6 劉燕;進入高原部隊習服狀況評價及促進習服的對策研究[D];第三軍醫(yī)大學;2011年

7 史新立;高溫環(huán)境下熱習服訓練實驗研究[D];天津大學;2014年

8 張玲燕;基于適應性規(guī)律的暈動習服研究[D];遼寧師范大學;2013年

9 鄭莉;熱習服對輻射復合濕熱環(huán)境動物損傷的影響及其機制的初步探討[D];第一軍醫(yī)大學;2004年

10 牛愛軍;孵化期熱習服對肉仔雞生長后期耐熱力影響的研究[D];山東師范大學;2006年

，

本文編號：2239294