本文選題：常染色體顯性多囊腎病 + 臨床表現(xiàn)�。� 參考：《第二軍醫(yī)大學(xué)》2016年博士論文

【摘要】：常染色體顯性多囊腎病(autosomal dominant polycystic kidney disease,ADPKD)(以下簡(jiǎn)稱多囊腎病)是人類最常見的單基因遺傳性腎病,發(fā)病率在0.1~0.25%,全世界約有1250萬患者,是導(dǎo)致終末期腎病(end-stage renal diseases,ESRD)的第四位病因,占5%~10%。其臨床特征突出表現(xiàn)為雙側(cè)腎臟發(fā)生無數(shù)進(jìn)行性增大的液性囊泡,損害腎臟的正常結(jié)構(gòu)和功能,50%以上患者在60歲時(shí)進(jìn)展至ESRD,需行透析或腎移植治療。該病除累及腎臟外,還可導(dǎo)致肝臟、胰腺、脾臟、泌尿生殖系統(tǒng)囊腫,心瓣膜病,結(jié)腸憩室和顱內(nèi)動(dòng)脈瘤等腎外病變。是一種嚴(yán)重危害人類健康且多系統(tǒng)受累的遺傳性疾病。ADPKD遺傳特點(diǎn)為代代發(fā)病,與性別無關(guān),子代發(fā)病機(jī)率均為50%,致病基因已被確認(rèn)為PKD1基因與PKD2基因。其中約85%患者因PKD1基因突變致病,約15%患者因PKD2基因突變致病;基因突變類型與疾病臨床表現(xiàn)密切相關(guān),PKD1基因致病患者其臨床表現(xiàn)及疾病進(jìn)展速度顯著重于PKD2基因突變患者。受基因檢測(cè)成本及技術(shù)檢出率限制,臨床診斷ADPKD主要依靠家族遺傳史+臨床表現(xiàn)+影像學(xué)檢查“三聯(lián)”法來確診。但已有臨床調(diào)查研究證實(shí),約10%~20%的臨床表現(xiàn)符合ADPKD患者無明確家族史。在這種情況下,單純依靠臨床表現(xiàn)進(jìn)行ADPKD診斷是否可靠?隨著新一代測(cè)序技術(shù)(next generation sequencing,NGS)的不斷發(fā)展,PKD1與PKD2基因突變的檢出能力不斷提高,但現(xiàn)有的各類基因診斷數(shù)據(jù)庫內(nèi)容均十分匱乏,幾乎沒有國(guó)內(nèi)人群檢測(cè)數(shù)據(jù)。既往研究顯示,ADPKD基因突變不存在突變熱點(diǎn),再聯(lián)系疾病的發(fā)病機(jī)制中的“二次打擊”“三次打擊”學(xué)說,我們推測(cè):在有家族史與無家族史(自發(fā)突變致病)的ADPKD患者間是否存在基因突變位點(diǎn)(和/或)類型上的差異,并伴隨有臨床表現(xiàn)差別。為了驗(yàn)證這一假設(shè),我們選擇2009年6月至2015年12月間在長(zhǎng)征醫(yī)院腎內(nèi)科長(zhǎng)期隨訪、臨床診斷明確的ADPKD患者,經(jīng)詢問病史、查看既往病例與影像學(xué)檢查結(jié)果、父母等直系親屬行超聲檢查確認(rèn)等方式,共篩選出有明確家族史ADPKD患者348例,確認(rèn)無家族史患者119例。統(tǒng)計(jì)結(jié)果顯示:無明確家族史ADPKD患者在多囊肝的發(fā)生率上顯著少于有明確家族史患者(p0.01),疾病診斷年齡平均較有明確家族史患者推遲2年,但沒有統(tǒng)計(jì)學(xué)差異。無家族史ADPKD患者在腦血管事件發(fā)生率上略低于有家族史患者(0.84%VS 1.44%),合并糖尿病發(fā)生率(1.68%VS 1.43%)相當(dāng),均無統(tǒng)計(jì)學(xué)差異。無家族史患者中兩人分別罹患胃癌及前列腺癌,兩組間在性別組成、高血壓發(fā)生率、治療情況及疾病進(jìn)展等其他方面均沒有統(tǒng)計(jì)學(xué)差異,僅發(fā)現(xiàn)≤18歲年齡組中無家族史患者估算腎小球?yàn)V過率(egfr)下降速度快于有家族史的患者(p0.05),41~50歲年齡組無家族史患者腎臟起始體積顯著小于有家族史患者(p0.05)。采用cox回歸分析顯示,患者所處年齡段(p=0.033)、診斷adpkd年齡(p=0.032)及有無家族史(p=0.026)是預(yù)測(cè)腎體積增長(zhǎng)率快速進(jìn)展的危險(xiǎn)因素。為進(jìn)一步比較兩組患者在疾病基因突變位點(diǎn)上的差異,我們從以上研究隊(duì)列中選取有或無明確家族史的患者各30例,進(jìn)行pkd1/2基因突變位點(diǎn)檢測(cè)。其中有家族史患者檢出致病突變位點(diǎn)28例,2例檢測(cè)結(jié)果為陰性,整體檢出率93.3%;無家族史adpkd患者pkd1/2基因突變位點(diǎn)檢測(cè)結(jié)果陽性者僅有20例(4例為可疑致病突變),在剩余未檢出pkd1/2基因致病突變的10例患者中額外實(shí)施了tsc、pkhd和hnf-1β三個(gè)可引起類似adpkd臨床及腎臟影像表現(xiàn)的基因突變檢測(cè),發(fā)現(xiàn)其中5例患者存在有pkhd1基因雜合突變,均為18歲以上成年人,未出現(xiàn)肝功能異常及肝硬化表現(xiàn),提示有復(fù)合雜合子遺傳等復(fù)雜遺傳模式參與了無家族史患者的疾病遺傳。仍有5例患者上述基因致病突變檢測(cè)結(jié)果呈陰性,基因致病突變整體檢出率為83.3%。在所有檢出的pkd1/2基因突變位點(diǎn)中,約47.9%為未見報(bào)道的新發(fā)突變,其中有家族史患者組發(fā)現(xiàn)11個(gè)新突變位點(diǎn),無家族史患者組檢出12個(gè),其中4例為可疑致病突變,因其屬于錯(cuò)義突變,且沒有家族史可供驗(yàn)證。所有檢出突變并未提示有突變熱點(diǎn)存在,基因檢測(cè)結(jié)果進(jìn)一步證實(shí)了臨床診斷在無家族史adpkd患者中的不確定性�；跈z出的明確基因致病突變,結(jié)合已有的技術(shù)條件,在這60例患者中,我們征得了其中6例育齡期患者及其配偶(5例有明確家族史,1例無明確家族史)的知情同意,實(shí)施胚胎植入前遺傳診斷(preimplantationgeneticdiagnosis,pgd)技術(shù)干預(yù)致病基因遺傳。通過藥物促排卵、體外卵胞漿內(nèi)單精子注射(intracytoplasmicsperminjectionicsi)授精,發(fā)育形成65個(gè)囊胚期胚胎,經(jīng)pgd檢測(cè)篩選出8個(gè)不攜帶致病基因、染色體正常的健康胚胎,為4例患者進(jìn)行了4個(gè)胚胎移植,最終有1例胚胎成功妊娠存活,發(fā)育至18周,胎兒宮內(nèi)發(fā)育正常,羊水穿刺結(jié)果確證為不攜帶致病基因遺傳胚胎。結(jié)果顯示,pgd技術(shù)安全可靠,對(duì)無明確家族史的adpkd夫婦而言,卵巢促排卵效果將直接決定pgd技術(shù)實(shí)施的可靠性及成功率。綜上所述,本研究發(fā)現(xiàn)有或無明確家族史、臨床診斷常染色體顯性多囊腎病患者在多囊肝、預(yù)測(cè)疾病進(jìn)展?fàn)顟B(tài)方面存在顯著差異,在此基礎(chǔ)上,抽取患者進(jìn)行pkd1/2基因檢測(cè),整體pkd1/2基因檢出率為80%,其中,有家族史患者檢出率為93.3%,新突變位點(diǎn)占39.3%;無家族史患者檢出率為66.7%,新突變位點(diǎn)占60%,其中檢出16.7%患者為非PKD基因突變致病。檢測(cè)結(jié)果極大的豐富了國(guó)內(nèi)人群ADPKD基因檢測(cè)信息數(shù)據(jù)庫,長(zhǎng)片段PCR+NGS基因檢測(cè)技術(shù)可靠、檢出率理想,是臨床診斷的有效武器。另一方面,無家族史臨床診斷ADPKD患者的PKD基因突變檢出率顯著降低(P=0.023),且檢出明確非PKD基因致病突變,這說明單純依靠臨床診斷ADPKD患者準(zhǔn)確性堪憂,有必要進(jìn)行PKD基因檢測(cè)以確診,并應(yīng)額外檢測(cè)可能導(dǎo)致出現(xiàn)與ADPKD類似臨床表現(xiàn)的基因突變。臨床表現(xiàn)的差異可能與ADPKD的診斷偏差有關(guān)。本研究最后應(yīng)用PGD操作使1對(duì)夫婦成功妊娠不攜帶致病基因突變的胚胎,證實(shí)了PGD技術(shù)在干預(yù)ADPKD疾病遺傳中的可操作性,為將來開展多中心干預(yù)研究及推廣應(yīng)用打下了良好的基礎(chǔ),為阻斷ADPKD遺傳、生育健康下一代提供了可靠的技術(shù)手段,必將取得巨大的社會(huì)效益。
[Abstract]:Autosomal dominant polycystic kidney disease (autosomal dominant polycystic kidney disease, ADPKD) (hereinafter referred to as polycystic kidney disease) is the most common monogenic hereditary nephropathy in humans. The incidence is in 0.1~0.25%, about 12 million 500 thousand patients all over the world. It is the fourth cause of end-stage renal disease (end-stage renal diseases, ESRD), which accounts for the clinical manifestation of 5%~10%.. It is characterized by a myriad of progressive fluid vesicles in the bilateral kidneys which damage the normal structure and function of the kidneys. More than 50% of the patients progressed to ESRD at the age of 60, requiring dialysis or renal transplantation. The disease could lead to the liver, pancreas, spleen, urogenital cysts, valvular disease, colonic diverticulum and cranium except for the kidney. The hereditary disease, such as internal aneurysm, is a hereditary disease.ADPKD hereditary disease which is serious harm to human health and multisystem. It is not related to sex, and the incidence of subgeneration is 50%. The pathogenic gene has been identified as PKD1 gene and PKD2 gene. About 85% of the patients are caused by the mutation of the PKD1 gene and about 15% of the patients are due to the PKD2 gene process. The type of gene mutation is closely related to the clinical manifestation of the disease. The clinical manifestation and disease progression of the patients with PKD1 gene are significantly higher than that of the PKD2 gene mutation patients. The cost of gene detection and the detection rate are limited. The clinical diagnosis ADPKD is mainly confirmed by the "triple" method of family genetic history + temporary bed performance + imaging examination. However, clinical studies have confirmed that the clinical manifestations of about 10%~20% are in line with the undefined family history of ADPKD patients. In this case, the reliability of ADPKD diagnosis by simply relying on clinical manifestations? With the continuous development of a new generation sequencing technology (next generation sequencing, NGS), the detection ability of PKD1 and PKD2 gene mutations is increasing, but The existing genetic diagnosis database is very scarce, and there are almost no domestic population detection data. Previous studies have shown that the ADPKD gene mutation does not have mutation hot spots, and then the "two hit" "three strikes" theory in the pathogenesis of the disease, we speculate that there is a family history and a family history of A (spontaneous mutation). In order to verify this hypothesis, we chose the long-term follow-up of the nephrology department of the Changzheng Hospital from June 2009 to December 2015, and the clinical diagnosis of ADPKD patients in the Long March Hospital from June 2009 to December 2015 to check the results of previous and imaging examinations, in order to verify this hypothesis. A total of 348 patients with a clear family history of ADPKD were selected and 119 cases were confirmed without family history. The statistical results showed that the incidence of polycystic liver disease in ADPKD patients without a clear family history was significantly less than that of patients with a clear family history (P0.01), and the average age of the diagnosis of the disease was more than that of a family history. It was delayed for 2 years, but there was no statistical difference. The incidence of cerebrovascular events in ADPKD patients without family history was slightly lower than that of patients with family history (0.84%VS 1.44%), and the incidence of diabetes (1.68%VS 1.43%) was similar. No statistical difference was found in the incidence of diabetes mellitus (1.43%). Among the patients without family history, two were respectively suffering from gastric cancer and prostate cancer, and the two groups were in sex composition and hypertension. There was no statistical difference in the incidence, treatment and disease progression. It was found that the estimated glomerular filtration rate (EGFR) decreased faster than the family history (P0.05) in the age group with no family history in the age group of the age of 18 (P0.05), and the initial volume of the renal viscera in the 41~50 age group was significantly smaller than that of the family history (P0.05). Ox regression analysis showed that the patient's age (p=0.033), the diagnosis of the ADPKD age (p=0.032) and the family history (p=0.026) were the risk factors for predicting the rapid progress of the renal volume growth rate. In order to further compare the difference between the two groups of patients at the mutation site of the disease, we choose a patient with or without a clear family history from the above cohort. The pkd1/2 gene mutation loci were detected in 30 cases, of which 28 cases were detected by family history, 2 cases were negative, and the overall detection rate was 93.3%. Only 20 cases (4 cases of suspected mutagenesis) were positive for pkd1/2 gene mutation and no pkd1/2 gene mutation was detected in the rest of the family history patients. In 10 patients, three additional mutations in TSC, pkhd and HNF-1 beta that could cause similar mutations in the clinical and renal imaging features of ADPKD were detected. 5 of them had PKHD1 gene heterozygous mutations, all of which were over 18 years old, without abnormal liver function and liver cirrhosis, suggesting complex heterozygote inheritance and other complex genetic patterns. There were 5 patients with no family history. 5 cases were still negative. The overall detection rate of the gene mutation was 83.3%. in all pkd1/2 mutation sites, and about 47.9% of the new mutations were unreported. Among them, the family history group found 11 new mutation sites, without family history. 12 cases were detected in the patient group, of which 4 were suspected to be pathogenic mutations because they were missense mutations, and there was no family Shi Ke for verification. All the mutations did not indicate the existence of mutation hot spots. The results of the gene detection further confirmed the inaccuracy of the clinical diagnosis in the ADPKD patients without family history. In these 60 patients, 6 of the 60 patients with childbearing age and their spouses (5 with a clear family history, 1 without a clear family history) were accepted, and the genetic diagnosis of preimplantation genetic diagnosis (preimplantationgeneticdiagnosis, PGD) was used to interfere with the genetic inheritance of the pathogenetic gene. 65 blastocysts were developed by insemination (intracytoplasmicsperminjectionicsi) insemination, and 8 healthy embryos that did not carry pathogenic genes and normal chromosomes were screened by PGD, and 4 embryos were transplanted for 4 patients. In the end, 1 embryos were successfully pregnant and developed to 18 weeks, fetal intrauterine development was normal, amniotic fluid was worn. The results showed that the PGD technology was safe and reliable. For ADPKD couples without a clear family history, the ovulation effect of the ovaries would directly determine the reliability and success rate of the implementation of PGD technology. In summary, this study found or had no definite family history and the clinical diagnosis of autosomal dominant polycystic kidney. On the basis of pkd1/2 gene detection, the overall pkd1/2 gene detection rate was 80%, among which, the detection rate of family history was 93.3%, the new mutation site was 39.3%, the detection rate of the patients without family history was 66.7% and the new mutation site was 60%, of which 16.7 was detected. % of the patients were non PKD gene mutations. The detection results greatly enriched the information database of ADPKD gene detection in domestic population, the long segment PCR+NGS gene detection technology was reliable, the detection rate was ideal, and it was an effective weapon in clinical diagnosis. On the other hand, the detection rate of PKD gene mutation in ADPKD patients without family history diagnosis was significantly lower (P=0.023). A clear non PKD gene mutation was detected. This indicates that the accuracy of the clinical diagnosis of ADPKD patients simply depends on the accuracy of the clinical diagnosis. It is necessary to make a diagnosis of the PKD gene, and the additional detection may lead to the mutation of the gene similar to the clinical manifestation of the ADPKD. The difference in clinical manifestation may be related to the diagnostic deviation of ADPKD. The final application of this study is to apply PGD exercise. In order to make the 1 couples successfully pregnant without the mutation of the pathogenic gene, the feasibility of the PGD technology in the intervention of the heredity of ADPKD disease has been confirmed, which has laid a good foundation for the future research and application of multi center intervention. It provides a reliable technical means for blocking the inheritance of ADPKD and the next generation of reproductive health. Social results.
【學(xué)位授予單位】：第二軍醫(yī)大學(xué)
【學(xué)位級(jí)別】：博士
【學(xué)位授予年份】：2016
【分類號(hào)】：R692

【相似文獻(xiàn)】

相關(guān)期刊論文 前10條

1 趙潔;夏慶華;;mTOR抑制劑在ADPKD中的應(yīng)用[J];泌尿外科雜志(電子版);2010年02期

2 原愛紅,梅長(zhǎng)林;肝細(xì)胞生長(zhǎng)因子對(duì)ADPKD囊腫襯里上皮細(xì)胞合成細(xì)胞外基質(zhì)、基質(zhì)金屬蛋白酶及其抑制劑的作用(英文)[J];第二軍醫(yī)大學(xué)學(xué)報(bào);2003年01期

3 鄧博;丁峰;;常染色體顯性多囊腎病的新認(rèn)識(shí)[J];腎臟病與透析腎移植雜志;2013年02期

4 金訊波;張智宇;;常染色體顯性遺傳多囊腎病發(fā)病機(jī)制的研究現(xiàn)狀[J];泌尿外科雜志(電子版);2010年03期

5 戴兵,孫田美,梅長(zhǎng)林,劉沙勤,吳玉梅,沈?qū)W飛,王文靖,湯兵;角質(zhì)細(xì)胞生長(zhǎng)因子在常染色體顯性遺傳性多囊腎病腎組織中的表達(dá)[J];中華內(nèi)科雜志;2005年05期

6 馬吉芳;郝麗榮;李納琦;;在常染色體顯性遺傳性多囊腎病家系中血管緊張素轉(zhuǎn)換酶基因多態(tài)性作用的研究[J];哈爾濱醫(yī)藥;2010年02期

7 吳玉梅,梅長(zhǎng)林,孫田美,章建全,張玲,宋吉,戴兵,湯兵;胰島素樣生長(zhǎng)因子在常染色體顯性遺傳性多囊腎病發(fā)病中的作用[J];中華腎臟病雜志;2004年04期

8 戎殳;梅長(zhǎng)林;金修才;姜紅;牛曉萍;;常染色體顯性多囊腎病患者動(dòng)脈形態(tài)學(xué)、力學(xué)與部分功能性參數(shù)研究[J];中華腎臟病雜志;2006年08期

9 王文娟;李莉;楊建一;;常染色體顯性遺傳型多囊腎病的研究進(jìn)展[J];中國(guó)優(yōu)生與遺傳雜志;2011年01期

10 王禹霄;張承巍;薛繼強(qiáng);畢敏;李春媚;;利用與PKD1緊密連鎖的微衛(wèi)星多態(tài)性對(duì)黑龍江省漢族人群進(jìn)行ADPKD的癥前診斷[J];現(xiàn)代生物醫(yī)學(xué)進(jìn)展;2011年18期

相關(guān)會(huì)議論文 前10條

1 賀津;王青松;葉建華;胡曉湘;李寧;;豬Pkd1基因的分子克隆與分析[A];中國(guó)遺傳學(xué)會(huì)模式生物與人類健康研討會(huì)會(huì)議論文集[C];2010年

2 夏丹;邵四海;汪朔;沈柏華;汪超軍;潘昊;蔡松良;謝立平;;后腹腔鏡和開放去頂減壓術(shù)治療[A];第十五屆全國(guó)泌尿外科學(xué)術(shù)會(huì)議論文集[C];2008年

3 毛志國(guó);梅長(zhǎng)林;沈?qū)W飛;戴兵;湯兵;吳玉梅;張樹忠;趙海丹;;角質(zhì)細(xì)胞生長(zhǎng)因子在常染色體顯性遺傳性多囊腎病發(fā)病中的作用及機(jī)制研究[A];2007年浙滬兩地腎臟病學(xué)術(shù)年會(huì)資料匯編[C];2007年

4 方力;華興;于莉娜;;常染色體顯性多囊腎病癌變臨床病理分析[A];中華醫(yī)學(xué)會(huì)病理學(xué)分會(huì)2006年學(xué)術(shù)年會(huì)論文匯編[C];2006年

5 張巖;劉亞偉;沈?qū)W飛;趙海丹;梅長(zhǎng)林;;常染色體顯性多囊腎病患者與正常成人尿液的定量比較蛋白質(zhì)組學(xué)分析[A];“中華醫(yī)學(xué)會(huì)腎臟病學(xué)分會(huì)2004年年會(huì)”暨“第二屆全國(guó)中青年腎臟病學(xué)術(shù)會(huì)議”論文匯編[C];2004年

6 張小鹿;王怡;;常染色體顯性遺傳多囊腎病中西醫(yī)發(fā)病認(rèn)識(shí)及診斷研究進(jìn)展[A];第十一屆全國(guó)中西醫(yī)結(jié)合腎臟病學(xué)術(shù)會(huì)議論文匯編[C];2010年

7 戴兵;劉亞偉;熊錫山;丁濤;鄒祝英;梅長(zhǎng)林;;羅格列酮長(zhǎng)期治療ADPKD動(dòng)物模型Han:SPRD大鼠療效及安全性評(píng)價(jià)[A];中華醫(yī)學(xué)會(huì)腎臟病學(xué)分會(huì)2006年學(xué)術(shù)年會(huì)論文集[C];2006年

8 戴兵;劉亞偉;熊錫山;丁濤;鄒祝英;梅長(zhǎng)林;;羅格列酮長(zhǎng)期治療ADPKD動(dòng)物模型Han:SPRD大鼠的療效及安全性評(píng)價(jià)[A];2007年浙滬兩地腎臟病學(xué)術(shù)年會(huì)資料匯編[C];2007年

9 牛丹;呂晶;譚峰;張亞莉;尹愛平;馮學(xué)亮;;多囊腎致終末期腎病的腹膜透析治療[A];中華醫(yī)學(xué)會(huì)腎臟病學(xué)分會(huì)2006年學(xué)術(shù)年會(huì)論文集[C];2006年

10 戎殳;梅長(zhǎng)林;李青;吳玉梅;費(fèi)麗萍;吳靜娣;葉朝陽;趙學(xué)智;張玉強(qiáng);張黎明;;271例常染色體顯性多囊腎病患者臨床分析[A];“中華醫(yī)學(xué)會(huì)腎臟病學(xué)分會(huì)2004年年會(huì)”暨“第二屆全國(guó)中青年腎臟病學(xué)術(shù)會(huì)議”論文匯編[C];2004年

相關(guān)博士學(xué)位論文 前10條

1 程明;二肽基肽酶4在常染色體顯性多囊腎病發(fā)病中的機(jī)制與作用研究[D];第二軍醫(yī)大學(xué);2016年

2 馬熠熠;常染色體顯性多囊腎病患者表現(xiàn)型與基因型分析及遺傳干預(yù)研究[D];第二軍醫(yī)大學(xué);2016年

3 劉沙勤;角質(zhì)細(xì)胞生長(zhǎng)因子在ADPKD腎囊腫組織中的表達(dá)及對(duì)囊腫襯里上皮細(xì)胞增殖作用的研究[D];第二軍醫(yī)大學(xué);2002年

4 周玉坤;多囊蛋白—2在腎組織中的表達(dá)及在ADPKD發(fā)病機(jī)制中的作用研究[D];第二軍醫(yī)大學(xué);2003年

5 戎殳;常染色體顯性多囊腎病動(dòng)脈功能研究[D];第二軍醫(yī)大學(xué);2007年

6 薛澄;常染色體顯性多囊腎病遺傳因素對(duì)疾病進(jìn)展的影響及治療策略的薈萃分析[D];第二軍醫(yī)大學(xué);2014年

7 崔心剛;腎移植前后常染色體顯性遺傳多囊腎的臨床與基礎(chǔ)研究[D];第二軍醫(yī)大學(xué);2004年

8 鄭瑞英;抗多囊蛋白-1單克隆抗體的制備及在ADPKD發(fā)病機(jī)理研究中的應(yīng)用[D];第二軍醫(yī)大學(xué);2000年

9 王文靖;富含半胱氨酸酸性分泌糖蛋白在常染色體顯性多囊腎病發(fā)病中的作用研究[D];第二軍醫(yī)大學(xué);2005年

10 張樹忠;漢族人常染色體顯性遺傳性多囊腎病1型致病基因突變檢測(cè)體系的建立及應(yīng)用[D];第二軍醫(yī)大學(xué);2003年

相關(guān)碩士學(xué)位論文 前10條

1 闕新祥;TGF-β1和VEGF在人多囊腎發(fā)病機(jī)制中的表達(dá)研究[D];山東大學(xué);2015年

2 韓樂天;骨橋蛋白在ADPKD腎臟中的表達(dá)及意義[D];山東大學(xué);2010年

3 陳輯;應(yīng)用基因芯片技術(shù)對(duì)ADPKD進(jìn)行基因診斷[D];山東大學(xué);2006年

4 秦均珍;應(yīng)用微衛(wèi)星DNA對(duì)常染色體顯性遺傳性多囊腎�。ˋDPKD）進(jìn)行癥狀前檢測(cè)及產(chǎn)前診斷的研究[D];廣西醫(yī)科大學(xué);2014年

5 王文儀;Shh信號(hào)通路在ADPKD發(fā)病機(jī)制中的作用[D];北京協(xié)和醫(yī)學(xué)院;2012年

6 葛守一;HMG GoA還原酶抑制劑對(duì)ADPKD囊腫襯里上皮細(xì)胞增殖抑制和凋亡誘導(dǎo)的研究[D];第二軍醫(yī)大學(xué);2001年

7 寧豪;COX-2在ADPKD腎臟致密斑和足細(xì)胞中的表達(dá)及意義[D];山東大學(xué);2008年

8 湯兵;轉(zhuǎn)化生長(zhǎng)因子β1在人常染色體顯性多囊腎病發(fā)病中的意義[D];第二軍醫(yī)大學(xué);2004年

9 吳玉梅;胰島素樣生長(zhǎng)因子在常染色體顯性遺傳性多囊腎病發(fā)病中的作用研究[D];第二軍醫(yī)大學(xué);2003年

10 邵建國(guó);CTGF和TGF-β1在ADPKD腎臟中的表達(dá)及意義[D];山東大學(xué);2012年

，

本文編號(hào)：2021192