张宏
肾脏病分子遗传方面
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- 姓名:张宏
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学术头衔:
博士生导师, 教育部“新世纪优秀人才支持计划”入选者
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学科领域:
内科学
- 研究兴趣:肾脏病分子遗传方面
张宏,女,40岁,北京大学副教授,副主任医师,硕士研究生导师,1989年毕业于原北京医科大学,1997年2月获国际肾脏病学会奖学金赴日本冈山大学医学部留学,获医学博士学位;2003,2004年先后两次受邀赴美国耶鲁大学进行合作研究。目前从事肾脏病分子遗传方面的研究,承担国家自然科学基金等科研课题7项,在JBC、JASN ,KI等国内外重要期刊发表论文30余篇,教育部新世纪人才基金获得者。
研究方向紧密抓住国际研究前沿,先后筛选获得了多个与肾小球硬化相关的差异表达基因。2000年发现并克隆了肾脏集合管特异性表达新基因 Collectrin ,证明该基因在肾脏的生长发育及病生理功能中具有重要作用,相关研究在国际权威杂志生物化学(JBC) 国际肾脏病杂志(KI)等发表。归国后2003原创性地发现克隆了我国第一个肾小球硬化相关新基因AngRem104,并证明该基因是血管紧张素II(AngII)刺激系膜细胞产生纤粘连蛋白增加、导致肾小球硬化的关键基因之一。同时充分利用国内资源建立了大型肾脏疾病临床-病理-基因数据库(),并在此基础上开展了常见肾脏疾病IgA肾病发病机制和遗传背景研究:与美国耶鲁大学合作首次对中国人家族性IgA肾病连锁定位,同时利用大样本散发病人开展有关IgA肾病易感基因、表型相关基因和进展相关基因等一系列研究。上述研究得到国际肾脏病学界肯定和认可,相关文章在肾脏病领域影响力最高的杂志美国肾脏病学会杂志(JASN)等杂志发表,由于其出色的研究成果先后四次受邀在国际肾脏病学术年会、国际IgA肾病会议做大会发言,曾获得国际肾脏病学会最佳研究报告一等奖,国际肾脏病学会最佳壁报兰丝带奖,获国家专利1项。
目前,张宏教授有关肾脏疾病相关基因的分离、克隆在国内领域属领先水平,形成了自己的研究方向和特色,她所从事的研究工作处于国际相应研究的前沿,具有明显的发展前景。
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【期刊论文】肾脏特异表达新基因Collectrin在大鼠5/6肾切除残余肾中的表达
张宏, 李寒, 王海燕
中华医学杂志,2003,83(8):684~687,-0001,():
-1年11月30日
目的探讨肾脏特异性表达新基因Collectrin在大鼠5/6肾切除残余肾组织中的表达变化,为Collectrin基因功能研究提供线索。方法建立慢性肾衰大鼠5/6肾切除模型,分为对照组(10只)、手术组(12只)和依那普利治疗组(12 只),采用逆转录2PCR和Western蛋白印迹、免疫组织化学技术检测手术后2、8和16周大鼠肾组织Collectrin的表达变化。结果在对照组中,随着大鼠周龄的增长大鼠Collectrin mRNA表达逐渐减少。2,8,16周分别为,11690109,1138±0104,1121±0109,(P<0105);在术后2,8,16周,手术组(2133±0107,1185±0120,1147±0117)Collectrin表达明显高于对照组(1169±0109,1138±0104,1121±0109,P<0105;经依那普利治疗,Collectrin 表达明显减少;手术组Collectrin的表达在手术后2周明显增加,随着慢性肾衰的进Collectrin的表达逐渐减少。2,8,16周分别为2133±0107,1185±0120,1147±0117(P<0105)。Collectrin蛋白的表达情况与Collectrin mRNA表达情况相一致。结论Collectrin的表达随大鼠周龄的增长而减少;在5/6肾切除残余肾组织中,Collectrin的表达与肾脏的增生、肥大的病生理变化相关。
基因表达, 增生, 肥大, 肾衰竭
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【期刊论文】人Collectrin同源基因的分离克隆及其在人肾集合管和远曲小管的特异表达
张宏, 和田淳, 李寒, 张艳玲, 桢野博史, 王海燕
中国生物人学与分子生物学报,2004,20(5):630~636,-0001,():
-1年11月30日
为探讨collectrin在人类疾病中的作用,利用人类collectrin同源性引物,经末端cDNA快速扩增法分离获得人collectrin基因全长序列并对collectrin 进行生物信息学分析及定位表达研究。结果发现,人类llectrin (GenBank 登录号为AF229179)基因全长含1345 bp,开放阅读框架编码222个氨基酸。在核苷酸和氨基酸水平,与小鼠collectrin序列分别有8619%和8714%同源性。生物信息学分析结果提示,collectrin为一个25kD的具有一个信号肽和一个跨膜区的跨膜糖蛋白。人类collectrin与人类血管紧张素转换酶相关的羧基肽酶(ACE2)具有4718%高度同源性。人多组织Northern杂交结果显示:collectrin基因为人类肾脏特异性表达基因。原位杂交及免疫组化证实,与小鼠collectrin 特异表达于集合管细胞不同,人collectrin基因mRNA及其蛋白产物除位于肾脏集合管细胞外,远曲肾小管细胞也有表达。由此推论,人类collectrin 基因为肾脏特异性表达基因,与人类血管紧张素转换酶相关的羧基肽酶具有高度同源性,可能为血管紧张素转换酶(ACE)基因家族的新成员。
collectrin, kidney, homology, specific expression, ACE2
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张宏, Xiubin LIANG, Hong ZHANG, Anyu ZHOU, Ping HOU, and Haiyan WANG
228 Hypertens Res Vol. 26, No.3 (2003),-0001,():
-1年11月30日
Accumulation of extracellular matrix (ECM) in the glomerular mesangium is a common feature of many progressive renal diseases. Angiotensin II (Ang II) plays a major role in the progression of chronic kidney diseases in part by induction of ECM. However, the precise molecular signals responsible for this effect are unknown. To explore possible molecular mechanisms of ECM production related to Ang II, we screened and identified genes up-regulated by Ang II in cultured human mesangial cells (MC). Detection of up-regulated genes was determined by mRNA populations from human MC with and without Ang II stimulation (10-6mol/l, 24h) by suppression subtractive hybridization. Reverse Northern blot analysis was performed to screen for differentially expressed genes. Full-length cDNAs of three novel genes were isolated by rapid amplification of cDNA ends (RACE)-polymerase chain reaction (PCR). One of these novel genes, AngRem104, was further investigated by Northern blot, Western blot and reverse transcription (RT)-PCR. The bioinformatics analysis implied that AngRem104 coded for a nuclear protein that was widely expressed in various normal human tissues. Moreover, up-regulation of ngRem104 induced by Ang II was time-dependent and was dosedependently blocked by the Ang II type 1 receptor antagonist, Losartan. Interestingly, we also demonstrated that AngReam104 was associated with increased fibronectin expression. We conclude that AngRem104 is a novel human gene that is related to the expression of fibronectin and that is up-regulated by Ang II in human MC. These findings may lead to new insights into the mechanisms of glomerular sclerosis associated with Ang II
angiotensin II, gene cloning, mesangial cells, extracellular matrix
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张宏, Hong Zhang, Jun Wada, Kazuyuki Hida, Yoshinori Tsuchiyama, Keita Hiragushi, Kenichi Shikata, Haiyan Wang
Vol. 276, No.20, Issue of May 18, pp. 17132-17139, 2001,-0001,():
-1年11月30日
Collectrin, a novel homolog of angiotensin-converting enzyme-related carboxypeptidase (ACE2), was identified during polymerase chain reaction-based cDNA subtraction and up-regulated in 5/6 ablated kidneys at hypertrophic phase. Collectrin, with 222 amino acids, has an apparent signal peptide and a transmembrane domain; the sequence is conserved in mouse, rat, and human and shares 81.9% identity. Human collectrin has 47.8% identity with non-catalytic extracellular, transmembrane, and cytosolic domains of ACE2; however, unlike ACE and ACE2, collectrin lacks active dipeptidyl carboxypeptidase catalytic domains. The collectrin mRNA transcripts are expressed exclusively in the kidney. In situ hybridization reveals its mRNA expression in renal collecting ducts, and immunohistochemistry shows that it is localized to the luminal surface and cytoplasm of collecting ducts. Immunoprecipitation studies, using [35S]methionine-labeled renal cortical and inner medullar collecting duct cells, i.e. M-1 and mIMCD-3, indicate that the protein size is; 32kDa. During the development of mouse kidney, mRNA signal is detectable at day 13 of gestation, and the protein product is observed in the ureteric bud branches. Its expression is progressively increased during later stages of the gestation extending into the neonatal periods and then is decreased in adult life. Up-regulated expression of collectrin in the hypertrophic kidneys after renal ablation and restricted spatio-temporal expression during development indicates a possible role (s) in the process of progressive renal failure and renal organogenesis.
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张宏, Bin Liang, Hong Zhang, An-Yu Zhou & Hai-Yan Wang
Biotechnology Letters 25: 139-142, 2003,-0001,():
-1年11月30日
AngRem104 is a novel gene recently identified in human mesangial cells induced by angiotensin II. cDNA microarray was performed to screen the functional genes related to AngRem104. Thirty-one genes were up-regulatedwhile 2 genes were down-regulated. Of all the up-regulated genes, fibronectin, one of the major extracellular matrixes, was up-regulated with over-expression of AngRem104.
angiotensin, cDNA microarray, mesangial cells
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张宏, XIUBIN LIANG, HONG ZHANG, ANYU ZHOU, and HAIYAN WANG
J Am Soc Nephrol 14: 1443-1451, 2003,-0001,():
-1年11月30日
Accumulation of extracellular matrix (ECM) in the glomerular mesangium is a common feature of many progressive renal diseases. Angiotensin II (AngII) plays important roles in the proliferation of glomerular mesangial cells (MC) as well as the synthesis of ECM such as fibronectin (FN) and collagens. However, the precise molecular signals responsiblefor these effects are unknown. To explore possible molecule mechanism of ECM accumulation related to AngII, suppression subtractive hybridization (SSH) was performed to screen and identify upregulated genes induced by AngII in cultured human MC. A novel gene, AngRem104 (GenBank accession number, AF367870), was isolated. The full-length cDNA of AngRem104 is 1690 bp, and it contains a 1041-bp open reading frame (ORF) encoding 347 amino acid residues with a predicted molecular mass of 37.2kD. AngRem104 widely expressed in human heart, placenta, liver, muscle, kidney, and pancreas. Moreover, AngRem104 was found in human glomeruli
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【期刊论文】Screening for genes up-regulated in 5/6 nephrectomized mouse kidney
张宏, HONG ZHANG, JUN WADA, YASHPAL S. KANWAR, YOSHINORI TSUCHIYAMA, KEITA HIRAGUSHI, KAZUYUKI HIDA, KENICHI SHIKATA, and HIROFUMI MAKINO
Kidney International, Vol. 56 (1999), pp. 549-558,-0001,():
-1年11月30日
Background. In diabetic and nondiabetic renal diseases, glo- merular hyperfiltration is believed to play a central role in the subsequent progression of glomerulosclerosis and interstitial renal scarring. To identify genes involved in the process of hyperfiltration and hypertrophy, a polymerase chain reaction (PCR)-based subtraction method, that is, representational dif-ference analysis of cDNA (cDNA-RDA), was employed. Methods. Ten-week-old ICR mice were 5/6 nephrectomized and sham operated. After two weeks, mRNAs were isolated from control and remnant kidneys and were subjected to the cDNA-RDA procedure. Results. We identified 10 known and 9 novel genes. Among 19 clones, 12 clones (8 known and 4 novel) showed 1.5-to 6-fold up-regulation by Northern blot analyses. The remaining seven clones were rarely expressed genes and were barely detected by Northern blot analyses, and their up-regulated expression was confirmed by Southern blot analysis using the PCR-amplified representative amplicons. The known genes in-cluded kidney androgen-regulated protein, major urinary pro-tein, lysozyme M, metalloproteinase-3 tissue inhibitor, chaper-onin 10, cytochrome oxidase I, e-sarcoglycan, ribosomal protein S3a, G-proteing10 subunit, and splicing factor 9G8. All of the isolated known genes have not been reported to be up-regu-lated in the nephrectomized mouse kidney and suggest the possible role of androgen action, mitochondrial functions, ma-trix metabolism, cell-matrix interactions, and intracellular sig-events in the initiation of the progressive renal injury of the remnant kidney. Furthermore, cDNA-RDA facilitates the discovery of novel genes, including two kidney-specific genes. Conclusions. The isolated known and novel genes may be involved in the pathobiological process of initialhyperfiltration and hypertrophy of remnant kidney.
nephrectomy, remnant kidney, gene expression, subtractive screening, glomerular hyperfiltration.,
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【期刊论文】Familial Interstitial Nephritis With Progressive Renal Failure
张宏, Hong Zhang, MD, Jun Wada, PhD, Kiyoto Nanba, Mie Kunitomi, Kazuyuki Hida, Yoshio Nagake, Kenichi Shikata, and Hirofumi Makino
American Journal of Kidney Diseases, Vol 36, No 4 (October), 2000,-0001,():
-1年11月30日
We describe a 53-year-old woman with chronic interstitial nephritis and asymptomatic impairment of renalfunction. Seven members of her family were suffering from renal failure and underwent emodialysis. At the time of their hospital admissions, they had shown evidence of end-stage renal failure at 40 to 50 years of age. Lack of proteinuria, hematuria, hypertension, hyperuricemia, hearing loss, and visual impairment were present before the deterioration of the renal function. Renal biopsy of the presented case indicated chronic interstitial nephritis without glomerular basement membrane abnormalities. Progressive decline of renal function and the inheritance pattern of autosomal dominance in this family suggested the diagnosis of familial interstitial nephritis. 2000 by the National Kidney Foundation, Inc.
Received February 9, accepted in revised formJune,
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【期刊论文】载脂蛋白(上3个氨基酸缺失)脂蛋白肾病相关的基因突变
张宏, 陈育青, 朱世乐, 邹万忠, 王梅, 刘章锁, 王海燕
中华医学杂志,2003,83(9):774~777,-0001,():
-1年11月30日
目的通过对3例脂蛋白肾病患者(其中2例为母子1例与他们无血缘关系)的载脂蛋白(apoE)基因的分析,研究脂蛋白肾病的发病机制。方法使用限制性酶切片段长度多态性的方法分析3例患者及其中一些家系成员的apoE的基因型,对患者的进行DNA测序。结果该3例脂蛋白肾病患者均携带一个apoE的突变体(3个氨基酸的缺失)结论该突变与脂蛋白肾病有关,在中国汉族人可能为脂蛋白肾病的致病性基因突变。
脂蛋白肾病, 载脂蛋白
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【期刊论文】血管紧张素Ⅱ上调人肾小球系膜细胞硬化相关基因的克隆
张宏, 周安宇, 梁秀彬, 侯平, 王海燕
中华肾脏病杂志,2002,18(2):140~145,-0001,():
-1年11月30日
目的筛选和鉴定培养的人肾小球系膜细胞(Mscj在血管紧张素Ⅱ(Angiotcnsin 1I,AngⅡ)作用下,产生以纤连蛋白(Fibronectin.FN)为代表的细胞外基质成分的过程中上调表达的基因,寻找AngII致细胞外基质堆积作用的相关基因,为探讨AngU在肾小球硬化发展过程的分子机制奠定基础。方法人MsC经Angn(10柚mol/L)刺激24h后,采用抑制性消减杂交(suppressfonsubtractive hybrJdiznlion,SSH)获得Angll描关的差异表达的eDNA,经纯化克隆到pGEM-Teasy Vector并转化大肠杆菌;随机选择120个克隆,经厦向Nortbern筛选上调表达的基因eDNA片段,并肚orthern杂交验证,然后进行DNA序列测定和同源性比较。采用5。一和3'-RACE及长距离PCR的方法获得新基因的全长eDNA。结果在120个随机选择的克胯中,反向Northern结果表明有55个克隆表达明显上调。挑选其中2十克隆进甜DNA序列测定,结果品示18个为独立的基必片段序列(有两个序列为双拷贝),其中15个为已知基冈,包括细胞外基质成分:如IIItd~板反应素I、I型胶原2;细胞骨架及结合蛋白:如平滑肌肌动蛋白d、钙凋蛋白I、1一胞浆型肌动蛋白等;合成和代谢相关蛋白:如醛缩酶A、延长因子1.1、arnesyl pyrophosphate synthetase等;噩白分解相关蛋白:如组织蛋白酶、泛索蛋白连接酶等。3个克隆(克隆104、52、46)与已知序列没有明品同源性,提示为新基因。3个新基因分别命名为AngRem(AngiolensinⅡrelated gencinmesaagial cells)104、AngRcm52、1gRein46,GenBank登录号分别为Ab367870、AY040225、AY040224。结论对已知基冈的分析表明,AngII对细胞外基质具有双重作用,即:既刺激培养的人Msc细胞外慕质成分表达上凋。也通过刺激PAl-I等分子的表达而抑制细胞外基质成分的降解。此外,我们还发现了目前尚未报告的与Angll对MaC的生物学效应一细胞外基质堆积和增生等作用辛H关的基四(包括3个新基因)。为揭示AngII介导的MsC在肾小球硬化进展过程的可能分子机制提供了新的线索。
血管紧张素11, 细胞外基质, 基因克隆, 系膜细胞, Ang Rcm
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