發(fā)布時間：2018-09-03 09:45

【摘要】：急性腎損傷（acute kidney injury,AKI）是由多種疾病引起的一種常見的臨床綜合征，是指由導致腎臟結構或功能變化的損傷引起的腎臟功能突然惡化。缺血再灌注損傷（ischemia reperfusion injury, IRI）是導致急性腎損傷的主要原因之一，具有較高的發(fā)病率和死亡率，伴隨著一系列的細胞事件發(fā)生，包括細胞壞死、細胞凋亡、炎癥細胞的浸潤和活性介質的釋放，從而導致組織損傷。 內質網(wǎng)（endoplasmic reticulum，ER）是真核細胞中具有重要作用的細胞器，它的主要作用是參與蛋白質的合成及轉運，各種蛋白的糖基化修飾以及鈣離子的儲存與分布等。細胞在多種理化因素（缺氧、饑餓、鈣離子平衡失調、化學毒物等）的刺激下，內質網(wǎng)腔內會出現(xiàn)蛋白質的錯誤折疊及未折疊蛋白質的聚集等現(xiàn)象，從而引起內質網(wǎng)功能紊亂，這種狀態(tài)稱為內質網(wǎng)應激（endoplasmic reticulum stress，ERS）。 腎臟缺血再灌注損傷是由于腎臟供血障礙引起的一種常見的應激性疾病，20世紀70年代由Glaumann等提出在恢復缺血后的腎臟的血液供應，可加重原有的單純由缺血所造成的損傷，并且指出缺血再灌注損傷的發(fā)病基礎是局部能量代謝障礙，發(fā)病的重要環(huán)節(jié)則是自由基產(chǎn)生和鈣超載。已經(jīng)證實，腎臟缺血再灌注損傷與內質網(wǎng)應激密切相關。在此過程中，組織的缺血缺氧、葡萄糖/營養(yǎng)物質匱乏、ATP耗竭、大量自由基的產(chǎn)生及鈣離子穩(wěn)態(tài)破壞等均可引起內質網(wǎng)功能障礙，觸發(fā)內質網(wǎng)應激。過度內質網(wǎng)應激通過破壞鈣離子穩(wěn)態(tài)、誘導細胞凋亡而加重缺血再灌注損傷，但其具體的機制一直沒有得到詳細闡述。最新研究發(fā)現(xiàn)，腎臟缺血再灌注損傷模型中，內質網(wǎng)源性轉錄因子CHOP，又名生長抑制DNA損傷基因153抗原（growth arrest and DNAdamage inducible153，GADDl53）表達升高，同時caspase-11的表達升高，造成腎臟功能的損害。據(jù)此，我們推測CHOP介導細胞凋亡在腎臟缺血再灌注損傷中起到重要作用。 本課題通過對野生型小鼠和CHOP敲除小鼠建立腎臟缺血再灌注損傷模型，探明CHOP在腎臟缺血再灌注損傷中的具體作用和機制，并進一步在體外實驗中培養(yǎng)人腎小管上皮細胞（HK-2）和人臍靜脈內皮細胞（HUVEC）并建立缺氧復氧損傷模型，驗證CHOP的重要作用及其分子機制，為闡明急性缺血性腎損傷發(fā)生機制以及尋找新的治療靶點提供科學依據(jù)。 1.實驗方法 1.1實驗動物 CHOP敲除小鼠由美國Jackson實驗室引進。體重22~26克的成年雄性野生型小鼠和CHOP敲除小鼠應用于本次試驗。實驗動物給于12小時晝夜交替飼養(yǎng)和自由的飲水、飲食。 1.2腎臟缺血再灌注損傷模型 實驗動物經(jīng)戊巴比妥鈉（60毫克/公斤）腹腔注射麻醉后，放置于安裝有控溫儀器的手術臺上，整個實驗過程中控制體溫在36℃左右。取腹正中切口，切除右腎，用防損傷微血管夾夾閉左側腎臟動、靜脈25分鐘。假手術組只分離腎蒂，切除右腎，未夾閉左側腎動靜脈。實驗動物在缺血再灌注24小時后經(jīng)腹主動脈穿刺取血及留取腎臟組織做進一步檢查分析。 1.3骨髓移植 供者、受者均選擇8~10周的雄鼠，受者經(jīng)鈷源60照射2次，總劑量10.5Gy，間隔4小時。在照射后2小時，由供者提取骨髓細胞按1×107個/只尾靜脈注射給受者。在骨髓移植后30天建立腎臟缺血再灌注損傷模型。 1.4細胞培養(yǎng)及缺氧復氧（HR）模型 人腎小管上皮細胞（HK-2）和人臍靜脈內皮細胞（HUVEC）培養(yǎng)在含有10%胎牛血清的DMEM中，放置于37°C，5%CO2的培養(yǎng)箱內。實驗鋪盤于6孔板內，按照5×105個細胞/孔。根據(jù)實驗方案，細胞放置于正常環(huán)境（5%CO2,21%O2和74%N2）和缺氧環(huán)境（5%CO2，1%O2和94%N2）。 1.5siRNA干擾的構建 CHOP的siRNA是由美國英杰生物技術公司合成、純化、退火。siRNA合成的具體序列為：GCUAGCUGAAGAGAAUGAATT；UUCAUUCUCUUCAGCUAGCTT。HK-2細胞和HUVECs按照80nM的質粒濃度運用Lipofectamin2000進行轉染干擾。 2.實驗結果 2.1CHOP在小鼠腎臟缺血再灌注損傷中介導細胞凋亡 2.1.1腎臟IR后CHOP、cleaved caspase-3蛋白表達情況 與對照組相比，腎臟IR后3小時開始CHOP、cleaved caspase-3蛋白表達升高，于再灌注6小時達高峰，并持續(xù)至24小時，均明顯高于對照組（p0.05）。 2.1.2CHOP敲除后cleaved caspase-3蛋白表達情況及生存率、腎功、病理的改變 cleaved caspase-3蛋白表達變化：CHOP敲除小鼠IR后6小時的cleaved caspase-3蛋白表達較野生型小鼠降低（p0.05）。 生存率的比較：CHOP敲除小鼠IR后生存率（80%）較野生型小鼠（0%）顯著提高（p0.05）。 腎功的比較：CHOP敲除小鼠IR后24小時血肌酐、血尿素氮均較野生型小鼠顯著降低（p0.05）。 病理的比較：CHOP敲除小鼠IR后24小時病理改變均較野生型小鼠顯著減輕（p0.05）。 2.1.3CHOP敲除通過影響腎臟微循環(huán)灌注減輕IR損傷 與野生型小鼠IR后相比，CHOP敲除能顯著改善缺血后腎臟早期的微循環(huán)灌注，從而減輕小鼠腎臟缺血再灌注損傷。 2.2骨髓移植證實腎臟固有細胞而不是骨髓來源的免疫細胞中CHOP介導IR中的細胞凋亡 2.2.1四組骨髓移植小鼠IR后生存率的改變 生存率的比較：四組骨髓移植小鼠IR后觀察7天，骨髓移植WT→WT小鼠生存率（0%）與骨髓移植CHOP-/-→WT小鼠生存率（0%）相比，，無統(tǒng)計學差異（p0.05）；骨髓移植WT→CHOP-/-小鼠生存率（80%）與骨髓移植CHOP-/-→CHOP-/-小鼠生存率（70%）相比，無統(tǒng)計學差異（p0.05）。 2.2.2四組骨髓移植小鼠IR后腎功的改變 腎功的比較：骨髓移植WT→WT小鼠與骨髓移植CHOP-/-→WT小鼠相比，IR后24小時的血肌酐、血尿素氮無統(tǒng)計學差異（p0.05）；骨髓移植WT→CHOP-/-小鼠與骨髓移植CHOP-/-→CHOP-/-小鼠，IR后24小時的血肌酐、血尿素氮無統(tǒng)計學差異（p0.05）。 2.2.3四組骨髓移植小鼠IR后病理的改變 病理的比較：骨髓移植WT→WT小鼠與骨髓移植CHOP-/-→WT小鼠相比，IR后24小時的病理改變無統(tǒng)計學差異（p0.05）；骨髓移植WT→CHOP-/-小鼠與骨髓移植CHOP-/-→CHOP-/-小鼠，IR后24小時的病理改變無統(tǒng)計學差異（p0.05）。 2.3腎小管上皮細胞及內皮細胞中CHOP介導細胞凋亡 2.3.1缺氧復氧引起腎小管上皮細胞損傷 LDH水平：與對照組相比，細胞上清LDH水平于HR后6小時增加，持續(xù)增加至復氧24小時（p0.05）。 CHOP蛋白表達：與對照組相比，HR后6小時升高，持續(xù)增加至24小時（p0.05）。 cleaved caspase-3蛋白表達：與對照組相比，HR后6小時升高，持續(xù)增加至24小時（p0.05）。 2.3.2缺氧復氧引起內皮細胞損傷 LDH水平：與對照組相比，細胞上清LDH水平于HR后6小時增加，持續(xù)至復氧24小時未見明顯下降（p0.05）。 CHOP蛋白表達：與對照組相比，HR后6小時升高，持續(xù)至復氧24小時未見明顯下降（p0.05）。 cleaved caspase-3蛋白表達：與對照組相比，HR后6小時升高，持續(xù)至復氧24小時未見明顯下降（p0.05）。 2.3.3CHOP基因沉默顯著減輕HR誘導的腎小管上皮細胞損傷 LDH水平：與HR24小時組比較，CHOP siRNA顯著減輕HR后腎小管上皮細胞損傷，細胞培養(yǎng)上清中LDH水平明顯下降（p0.05）。 CHOP siRNA顯著抑制HR誘導的腎小管上皮細胞CHOP蛋白的表達（p0.05）。 CHOP基因沉默可顯著抑制HR后24小時腎小管上皮細胞cleaved caspase-3的蛋白的表達（p0.05）。 2.3.4CHOP基因沉默顯著減輕HR誘導的內皮細胞損傷 LDH水平：與HR6小時組比較，CHOP siRNA顯著減輕HR內皮細胞損傷，細胞培養(yǎng)上清中LDH水平明顯下降（p0.05）。 CHOPsiRNA顯著抑制HR誘導的內皮細胞CHOP蛋白的表達（p0.05）。 CHOP基因沉默可顯著抑制HR后6小時內皮細胞cleaved caspase-3蛋白的表達（p0.05）。 3.結論 腎臟固有細胞中的CHOP的激活在介導腎臟IR損傷中的細胞凋亡、腎臟功能損害起到重要作用，而敲除固有細胞中的CHOP后細胞凋亡減少，腎臟功能得到一定的保護。
[Abstract]:Acute kidney injury (AKI) is a common clinical syndrome caused by a variety of diseases. It refers to the sudden deterioration of renal function caused by the damage of kidney structure or function. Ischemia reperfusion injury (IRI) is one of the main causes of acute kidney injury and has a high incidence. Morbidity and mortality are accompanied by a series of cellular events, including cell necrosis, apoptosis, infiltration of inflammatory cells and release of active mediators, leading to tissue damage.
Endoplasmic reticulum (ER) is an important organelle in eukaryotic cells. It plays an important role in the synthesis and transport of proteins, glycosylation modification of proteins and the storage and distribution of calcium ions. Endoplasmic reticulum stress (ERS) is a state of endoplasmic reticulum stress (ERS) in which misfolded and unfolded proteins accumulate in the endoplasmic reticulum.
Renal ischemia-reperfusion injury is a common stress disease caused by renal dysfunction of blood supply. Glaumann et al. proposed in the 1970s that restoring the blood supply of the kidney after ischemia could aggravate the original injury caused by ischemia alone, and pointed out that the pathogenesis of ischemia-reperfusion injury is based on the impairment of local energy metabolism. It has been proved that renal ischemia-reperfusion injury is closely related to endoplasmic reticulum stress. In this process, tissue ischemia-hypoxia, glucose/nutrient deficiency, ATP depletion, large amount of free radicals production and calcium homeostasis damage can cause endoplasmic reticulum dysfunction, triggering. Endoplasmic reticulum stress. Excessive endoplasmic reticulum stress aggravates ischemia-reperfusion injury by destroying calcium homeostasis and inducing apoptosis, but its specific mechanism has not been elaborated in detail. The expression of owth arrest and DNA damage inducible 153 (GADDl53) was elevated, while the expression of caspase-11 was elevated, resulting in damage to renal function.
In this study, we established a renal ischemia-reperfusion injury model in wild type mice and CHOP knockout mice to explore the specific role and mechanism of CHOP in renal ischemia-reperfusion injury, and further cultured human renal tubular epithelial cells (HK-2) and human umbilical vein endothelial cells (HUVEC) in vitro and established a hypoxia-reoxygenation injury model. The important role of CHOP and its molecular mechanism provide scientific basis for elucidating the pathogenesis of acute ischemic renal injury and searching for new therapeutic targets.
1. experimental method
1.1 experimental animals
CHOP knockout mice were imported from Jackson Laboratory of USA. Adult male wild type mice weighing 22-26 g and CHOP knockout mice were used in this experiment. The experimental animals were fed day and night for 12 hours and fed free water and diet.
1.2 renal ischemia-reperfusion injury model
After anesthesia with sodium pentobarbital (60 mg/kg), the animals were placed on the operating table equipped with a thermostat. During the whole experiment, the body temperature was controlled at about 36 C. The right kidney was removed through a median abdominal incision, and the left renal artery and vein were clamped with a protective microvascular clip for 25 minutes. Left renal artery and vein were not clamped. Blood samples were taken from abdominal aorta and kidney tissues were taken for further examination 24 hours after ischemia and reperfusion.
1.3 bone marrow transplantation
The recipients were irradiated with cobalt 60 twice at a total dose of 10.5 Gy at intervals of 4 hours. Two hours after irradiation, bone marrow cells were extracted from the donor and injected into the recipient by 1 *107 cells per caudal vein. A renal ischemia-reperfusion injury model was established 30 days after bone marrow transplantation.
1.4 cell culture and anoxia reoxygenation (HR) model
Human renal tubular epithelial cells (HK-2) and human umbilical vein endothelial cells (HUVEC) were cultured in DMEMs containing 10% fetal bovine serum and placed in incubators with 37 C and 5% CO2. The cells were placed in 6-well plates with 5 105 cells/pores. According to the experimental scheme, the cells were placed in normal (5% CO2, 21% O2 and 74% N2) and hypoxic (5% CO2, 1% O2 and 94% N2).
Construction of 1.5siRNA interference
The siRNA of CHOP was synthesized, purified and annealed by Yingjie Biotechnology Company, USA. The specific sequence of siRNA synthesis was GCUAGGAAUGAATT, UUCUCUUCAGCUAGCTT.HK-2 cells and HUVECs were transfected with Lipofectamin 2000 at 80nM plasmid concentration.
2. experimental results
2.1CHOP mediates apoptosis in renal ischemia-reperfusion injury in mice
Expression of CHOP and cleaved caspase-3 protein in 2.1.1 kidneys after IR
Compared with the control group, the expression of cleaved caspase-3 protein increased at the beginning of CHOP 3 hours after IR, reached the peak at 6 hours after reperfusion, and lasted for 24 hours, which was significantly higher than that of the control group (p0.05).
Cleaved caspase-3 protein expression and survival rate, renal function and pathological changes after 2.1.2CHOP knockout
Changes of cleaved caspase-3 protein expression: The expression of cleaved caspase-3 protein in CHOP knockout mice 6 hours after IR was lower than that in wild type mice (p0.05).
Survival rate: the survival rate of CHOP knockout mice after IR (80%) was significantly higher than that of wild type mice (0%) (P0.05).
Comparison of renal function: CHOP knockout mice 24 hours after IR serum creatinine, blood urea nitrogen were significantly lower than wild type mice (p0.05).
Pathological comparison: the pathological changes of CHOP knockout mice were significantly reduced at 24 hours after IR (P0.05).
2.1.3CHOP knockout reduces IR damage by affecting renal microcirculation perfusion
CHOP knockout significantly improved the early microcirculatory perfusion of ischemic kidneys, thereby reducing the renal ischemia-reperfusion injury in mice compared with wild-type mice after IR.
2.2 Bone marrow transplantation confirms that CHOP mediates apoptosis in IR in renal innate cells rather than in bone marrow-derived immune cells
Changes in survival rate after IR in 2.2.1 four groups of bone marrow transplant mice
Survival rate of four groups of bone marrow transplantation mice after IR observation 7 days, bone marrow transplantation WT WT mice survival rate (0%) and bone marrow transplantation CHOP -/- WT mice survival rate (0%) compared with no significant difference (p0.05); bone marrow transplantation WT CHOP -/- mice survival rate (80%) and bone marrow transplantation CHOP -/- CHOP /- mice survival rate (70%) compared with no significant difference. Difference (P0.05).
Changes in renal function after 2.2.2 IR in four groups of bone marrow transplant mice
Comparison of renal function: There was no significant difference in serum creatinine and blood urea nitrogen between bone marrow transplanted WT WT mice and bone marrow transplanted CHOP -/- WT mice 24 hours after IR (p0.05); there was no significant difference in serum creatinine and blood urea nitrogen between bone marrow transplanted WT CHOP -/- mice and bone marrow transplanted CHOP -/ CHOP -/- mice 24 hours after IR (p0.05).
Pathological changes of 2.2.3 four groups of bone marrow transplantation mice after IR
Pathological comparison: BMT WT WT mice and BMT CHOP -/- WT mice had no significant difference in pathological changes 24 hours after IR (p0.05); BMT WT CHOP -/- mice and BMT CHOP -/- mice, there was no significant difference in pathological changes 24 hours after IR (p0.05).
2.3, CHOP mediated apoptosis in renal tubular epithelial cells and endothelial cells.
Injury of renal tubular epithelial cells induced by 2.3.1 hypoxia reoxygenation
LDH level: Compared with the control group, the level of LDH in cell supernatant increased 6 hours after HR and continued to increase to 24 hours after reoxygenation (p0.05).
CHOP protein expression: compared with the control group, HR increased after 6 hours, and increased to 24 hours (P0.05).
Cleaved caspase-3 protein expression: compared with the control group, 6 hours after HR increased, continued to increase to 24 hours (p0.05).
Endothelial cell injury induced by 2.3.2 hypoxia reoxygenation
LDH level: Compared with the control group, the level of LDH in cell supernatant increased 6 hours after HR and did not decrease significantly until 24 hours after reoxygenation (p0.05).
CHOP protein expression: Compared with the control group, HR increased at 6 hours and remained unchanged until 24 hours after reoxygenation (p0.05).
Cleaved caspase-3 protein expression: compared with the control group, HR increased at 6 hours and did not decrease significantly until 24 hours after reoxygenation (p0.05).
2.3.3CHOP gene silencing significantly alleviated HR induced renal tubular epithelial cell injury
LDH level: Compared with HR 24 hours group, CHOP siRNA significantly reduced the injury of renal tubular epithelial cells after HR, and the LDH level in cell culture supernatant decreased significantly (p0.05).
CHOP siRNA significantly inhibited the expression of CHOP protein in renal tubular epithelial cells induced by HR (P0.05).
CHOP gene silencing significantly inhibited the expression of cleaved caspase-3 protein in renal tubular epithelial cells 24 hours after HR (p0.05).
2.3.4CHOP gene silencing significantly alleviated endothelial cell injury induced by HR
LDH level: Compared with HR6-hour group, CHOP siRNA significantly reduced the injury of HR endothelial cells, and LDH level in cell culture supernatant decreased significantly (p0.05).
CHOPsiRNA significantly inhibited HR induced CHOP protein expression in endothelial cells (P0.05).
CHOP gene silencing significantly inhibited the expression of cleaved caspase-3 protein in endothelial cells 6 hours after HR (P0.05).
3. conclusion
The activation of CHOP in intrinsic cells of kidney plays an important role in mediating apoptosis and impairment of renal function in IR injury of kidney.
【學位授予單位】：吉林大學
【學位級別】：博士
【學位授予年份】：2014
【分類號】：R692.5

【相似文獻】

相關期刊論文 前10條

1 金梅良;CHOP治療NHL致腫瘤溶解綜合癥死亡1例[J];腫瘤防治研究;1997年05期

2 李虎生;張華;陶曉明;;利妥昔單抗聯(lián)合CHOP方案治療26例B細胞性淋巴瘤的臨床分析[J];華夏醫(yī)學;2009年03期

3 李濤;蘇炳光;凌華晃;蔡茂德;吳祥成;;CHOP和CHOEP方案治療非霍奇金淋巴瘤的臨床觀察[J];中華腫瘤防治雜志;2007年13期

4 向華,王堅,孫孟紅,陸磊,水若鴻,朱雄增;黏液樣/圓細胞型脂肪肉瘤石蠟包埋組織中FUS-CHOP融合基因檢測的臨床病理學意義[J];中華病理學雜志;2005年01期

5 謝哲,黃達仁;CHOP方案治療惡性淋巴瘤32例臨床分析[J];海南醫(yī)學;2005年05期

6 張靜;徐敬根;;美羅華聯(lián)合CHOP方案治療B細胞性非霍奇金淋巴瘤療效觀察[J];當代醫(yī)學;2011年10期

7 黎軍和;氟達拉濱、CAP和ChOP方案治療938例初治B期和C期慢性淋巴細胞白血病療效的隨機比較[J];國外醫(yī)學.內科學分冊;2002年10期

8 黃春暉;孫守金;謝鳳玲;;放療聯(lián)合CHOP(或類似方案)化療治療鼻腔非霍奇金淋巴瘤12例療效觀察[J];臨床醫(yī)藥實踐;2009年17期

9 黃春暉;孫守金;謝鳳玲;;放療聯(lián)合CHOP(或類似方案)化療治療鼻腔非霍奇金淋巴瘤12例療效觀察[J];臨床醫(yī)藥實踐;2009年18期

10 林友;;CHOP-R方案聯(lián)合治療復發(fā)性彌漫大B細胞性淋巴瘤六例療效觀察[J];海南醫(yī)學;2010年10期

相關會議論文 前10條

1 趙勝;陳欣林;田志云;Jack Rychik;;CHOP評分診斷雙胎輸血綜合征的應用研究[A];中國超聲醫(yī)學工程學會第三屆全國婦產(chǎn)及計劃生育超聲醫(yī)學學術會議論文匯編[C];2010年

2 王曉雪;李艷;;美羅華聯(lián)合CHOP方案與CHOP方案治療Ⅲ、Ⅳ期彌漫大B細胞性淋巴瘤的臨床對比研究[A];全國中西醫(yī)結合血液學學術會議論文匯編[C];2010年

3 ;The Effect of Endoplasmic Reticulum Stress Protein CHOP on Cyclosporine A-induced Injury of Glomerular Endothelial Cells[A];第八屆海峽兩岸心血管科學研討會論文集[C];2011年

4 馬孝甜;孫麗洲;;子癇前期內質網(wǎng)應激相關蛋白CHOP/GADD153的表達及其意義[A];中華醫(yī)學會第三次全國妊娠期高血壓疾病學術研討會論文匯編[C];2011年

5 宋娟;;美羅華聯(lián)合CHOP方案治療彌漫性大B細胞性淋巴瘤的護理[A];全國護理教育研討會暨第2次護理學院（校）長論壇論文集[C];2010年

6 李光乾;王海萍;;驚厥持續(xù)狀態(tài)幼年大鼠海馬中GRP78、CHOP的表達及依達拉奉對其影響(摘要)[A];2011年浙江省醫(yī)學會兒科學分會學術年會暨兒內科疾病診治新進展國家級學習班論文匯編[C];2011年

7 張立;羅百靈;何白梅;袁婷;胡成平;;HO-1對香煙煙霧提取物誘導的支氣管上皮細胞凋亡及CHOP表達的調節(jié)作用[A];中華醫(yī)學會呼吸病學年會——2011（第十二次全國呼吸病學學術會議）論文匯編[C];2011年

8 管忠震;;惡性淋巴瘤的治療進展[A];中華醫(yī)學會第八次全國血液學學術會議論文匯編[C];2004年

9 王亞蘭;王曉紅;于煥欣;;沙利度胺聯(lián)合CHOP方案治療52例侵襲性非霍奇金淋瘤臨床對照研究[A];第十一屆中國抗癌協(xié)會全國淋巴瘤學術大會教育論文集[C];2009年

10 宋小英;潘建蘭;;CHOP方案化療治療骨原發(fā)性非何杰金淋巴瘤的護理[A];2006年貴州省醫(yī)學會骨科學分會學術年會論文匯編[C];2006年

相關重要報紙文章 前10條

1 本報特約撰稿人 欒雪梅;大劑量化療+干細胞移植優(yōu)于常規(guī)化療[N];醫(yī)藥經(jīng)濟報;2004年

2 駐京記者 賈巖;治療年輕DLBCL患者,哪種方案好[N];醫(yī)藥經(jīng)濟報;2010年

3 劉元江;利妥昔單抗聯(lián)合CHOP治療彌漫大B細胞淋巴瘤的成本－效果分析[N];醫(yī)藥經(jīng)濟報;2005年

4 樓南星;年少不輕狂 網(wǎng)絡寫精彩[N];經(jīng)理日報;2003年

5 徐茜茜 吳靜 胡澤團;我是CCS一員[N];中國水運報;2004年

6 本報記者 慕欣;如何選擇B/T——LBL/ALL診治方案[N];醫(yī)藥經(jīng)濟報;2010年

7 古今;手表 年輕風潮擋不住[N];中國礦業(yè)報;2002年

8 天津醫(yī)科大學附屬腫瘤醫(yī)院淋巴腫瘤科主任 王華慶;惡性淋巴瘤 診治主旋律變化進行時[N];健康報;2010年

9 張化;歐洲珠寶市場變臉[N];國際經(jīng)貿消息;2001年

10 青鋒;抗非何杰金淋巴瘤單克隆抗體顯功效[N];醫(yī)藥經(jīng)濟報;2001年

相關博士學位論文 前10條

1 董彪;內質網(wǎng)源性轉錄因子CHOP在腎臟缺血再灌注損傷中的作用和機制研究[D];吉林大學;2014年

2 吳婷婷;X盒結合蛋白1在糖尿病心肌病心肌細胞凋亡中的作用機制研究[D];山東大學;2012年

3 景寶;PTEN敲除小鼠前列腺癌模型的蛋白組學分析靶基因Chop的確定及誘導性表達c-myc細胞系的建立[D];天津醫(yī)科大學;2013年

4 張亞妮;Zhangfei基因在細胞內質網(wǎng)應激反應中的生物功能研究[D];西北農(nóng)林科技大學;2010年

5 李惠玲;大鼠視網(wǎng)膜再灌注損傷致細胞凋亡的內質網(wǎng)應激機制研究[D];中南大學;2006年

6 申向民;鼠腦缺血再灌后神經(jīng)元凋亡的內質網(wǎng)應激機制及依達拉奉的影響[D];中南大學;2007年

7 曲鵬;NGF和CGRP對局灶性腦缺血再灌注大鼠皮質神經(jīng)元P38MAPK，CHOP及IL-1β表達的調節(jié)作用[D];中國醫(yī)科大學;2007年

8 劉光輝;內質網(wǎng)應激在糖尿病腎損害中的作用機制研究[D];山東大學;2010年

9 徐利明;原發(fā)縱隔B細胞淋巴瘤綜合治療及調強放療結果和劑量分析[D];北京協(xié)和醫(yī)學院;2013年

10 熊學華;載脂蛋白E對創(chuàng)傷性顱腦損傷后內質網(wǎng)應激的影響及意義[D];重慶醫(yī)科大學;2013年

相關碩士學位論文 前10條

1 王曉雪;美羅華聯(lián)合CHOP方案與CHOP方案治療Ⅲ、Ⅳ期彌漫大B細胞性淋巴瘤的臨床對比研究[D];中國醫(yī)科大學;2010年

2 李楠;蛋白酶體抑制劑硼替佐米通過內質網(wǎng)應激調亡途徑CHOP誘導人腦膠質瘤細胞凋亡的機制研究[D];山西醫(yī)科大學;2011年

3 楊寧寧;美羅華聯(lián)合CHOP方案與CHOP方案治療B細胞非霍奇金淋巴瘤的臨床對比研究[D];山東大學;2012年

4 趙振慧;CHOP方案一線治療維、漢不同亞型DLBCL的療效觀察[D];新疆醫(yī)科大學;2013年

5 王麗玲;FND與CHOP方案治療惰性淋巴瘤的臨床分析[D];新疆醫(yī)科大學;2010年

6 童玉娜;內質網(wǎng)源性轉錄因子CHOP在缺氧復氧誘導腎小管上皮細胞炎癥反應中的作用和機制研究[D];第三軍醫(yī)大學;2011年

7 黃若新;不同化療方案治療初治彌漫大B細胞淋巴瘤的療效觀察[D];福建醫(yī)科大學;2010年

8 胡炳俊;轉hIAPP和CHOP基因調控小鼠β細胞凋亡的研究[D];中國農(nóng)業(yè)科學院;2013年

9 周哲;一氧化碳和內質網(wǎng)應激蛋白CHOP在環(huán)孢霉素A引起的腎小球內皮細胞損傷中的作用[D];寧夏醫(yī)科大學;2011年

10 裴菲;內質網(wǎng)應激蛋白（BiP、CHOP）在多囊卵巢綜合征患者血白細胞中表達的研究[D];安徽醫(yī)科大學;2013年

本文編號：2219616