张学
博士研究生 教授
哈尔滨医科大学
主要从事单基因遗传病致病基因和肿瘤遗传学研究。
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- 姓名:张学
- 目前身份:在职研究人员
- 担任导师情况:
- 学位:
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学术头衔:
博士生导师, 国家杰出青年科学基金获得者,
- 职称:高级-教授
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学科领域:
基础医学
- 研究兴趣:主要从事单基因遗传病致病基因和肿瘤遗传学研究。
张学,男,1964年7月生,黑龙江省肇州县人,医学遗传学教授,博士生导师,现任哈尔滨医科大学校长、党委副书记,黑龙江省医学科学院院长。
1986年中国医科大学临床医学专业本科毕业,1989年获中国医科大学遗传学专业硕士学位,1994年获中国医科大学细胞生物学专业博士学位。1989年-2002年先后任中国医科大学基础医学院医学遗传学教研室助教、讲师、教授及细胞生物学教研室主任,2001年至今任中国医学科学院基础医学研究所-北京协和医学院基础学院医学遗传学系主任,2002年-2009年任中国医学科学院院长助理-北京协和医学院校长助理,2009年-2013年任中国医学科学院-北京协和医学院研究生院副院长,2013年-2014年任中国医学科学院-北京协和医学院科技管理处处长,2014年-2017年任中国医学科学院基础医学研究所-北京协和医学院基础学院党委书记。2017年4月任中国医学科学院副院长、北京协和医学院副校长。2018年9月任哈尔滨医科大学校长、党委副书记,黑龙江省医学科学院院长。
主要从事单基因病和基因组病的分子遗传学研究,发现了家族性反常性痤疮等单基因病的致病基因和先天性全身多毛症等基因组病的致病DNA重排,揭示了基因抑制性上游开放阅读框致病突变和回文结构介导的染色体插入两种新机制,在Science、Nature Genetics和Am J Hum Genet等杂志发表系列高水平论文。2001年获国家杰出青年科学基金,2011年获谈家桢生命科学创新奖,2014年以第一完成人获国家自然科学二等奖,2017年获何梁何利医学药学奖、全国创新争先奖。
兼任中国医师协会医学遗传医师分会会长,中华医学会医学遗传学分会名誉主任委员,《中华医学遗传学杂志》主编,国家卫生健康委员会罕见病诊疗与保障专家委员会主任委员,国务院学位委员会学科评议组成员,中国学位与研究生教育学会副会长,中华预防医学会副会长。
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成果数
19
【期刊论文】Somatic mutation analysis of p53 and ST7 tumor suppressor genes in gastric carcinoma by DHPLC
张学, Chong Lu, Hui-Mian Xu, Qun Ren, Yang Ao, Zhen-Ning Wang, Xue Ao, Li Jiang, Yang Luo, Xue Zhang
World J Gastroenterol 2003; 9 (12): 2662-2665,-0001,():
-1年11月30日
AIM: To verify the effectiveness of denaturing highperformance liquid chromatography (DHPLC) in detecting somatic mutation of p53 gene in gastric carcinoma tissues. The superiority of this method has been proved in the detection of germline mutations, but it was not very affirmative with respect to somatic mutations in tumor specimens. ST7 gene, a candidate tumor suppressor gene identified recently at human chromosome 7q31.1, was also detected because LOH at this site has also been widely reported in stomach cancer. METHODS: DNA was extracted from 39 cases of surgical gastric carcinoma specimen and their correspondent normal mucosa. Seven fragments spanning the 11 exons were used to detect the mutation of p53 gene and the four exons reported to have mutations in ST7 gene were amplified by PCR and directly analyzed by DHPLC without mixing with wild-type allele. RESULTS: In the analysis of p53 gene mutation, 9 aberrant DHPLC chromatographies were found in tumor tissues, while their normal-adjacent counterparts running in parallel showed a normal shape. Subsequent sequencing revealed nine sequence variations, 1 polymorphism and 8 mutations including 3 mutations not reported before. The mutation rate of p53 gene (21%) was consistent with that previously reported. Furthermore, no additional aberrant chromatography was found when wild-type DNA was added into the DNA of other 30 tumor samples that showed normal shapes previously. The positivity of p53 mutations was significantly higher in intestinal-type carcinomas (40%) than that in diffuse-type (8.33%) carcinomas of the stomach. No mutation of ST7 gene was found. CONCLUSION: DHPLC is a very convenient method for the detection of somatic mutations in gastric carcinoma. The amount of wild type alleles supplied by the non-tumorouscells in gastric tumor specimens is enough to form heteroduplex with mutant alleles for DHPLC detection. ST7 gene may not be the target gene of inactivation at 7q31 site in gastric carcinoma.
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【期刊论文】SHORT REPORT A highly conserved processed PTEN pseudogene is located on chromosome band 9p21
张学, Patricia LM Dahia, , Michael G FitzGerald, Xue Zhang, Debbie J Marsh, Zimu Zheng, Torsten Pietsch, Andreas von Deimling, Frank G Haluska, Daniel A Haber, and Charis Eng
Oncogene (1998) 16, 2403-2406,-0001,():
-1年11月30日
PTEN/MMAC1/TEP1, encoding a dual-specificity phosphatase, is a tumor suppressor gene which has recently been cloned and mapped to chromosome 10q23.3. We have shown that germline mutations of PTEN are present in individuals with two hamartoma syndromes: Cowden Syndrome, associated with a predisposition to breast and thyroid cancers, and Bannayan-Zonana syndrome. Somatic mutations of PTEN have been reported in a variety of human cancer cell lines, suggesting a potential role for this gene in the pathogenesis of human malignancies. We report the identification of a highly conserved PTEN processed pseudogene, cPTEN, which shares over 98% homology with the coding region of functional PTEN, and its localisation to chromosome 9p21. The high sequence homology of cPTEN with the PTEN transcript may potentially lead to misinterpretation when performing mutation analyses based on cDNA templates. Caution should be exerted when using such screening approaches.
MMAC1, TEP1, 9p, Cowden, pseudogene
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【期刊论文】DELETION OF THREE DISTINCT REGIONS ON CHROMOSOME 13qIN HUMAN NON-SMALL-CELL LUNG CANCER
张学, Kenji TAMURA, Xue ZHANG, Yoshinori MURAKAMI, Setsuo HIROHASHI, Hong-Ji XU, Shi-Xue HU, William F. BENEDICT and Takao SEKIYA*
Int. J. Cancer (Pred. Oncol.): 74, 45-49 (1997),-0001,():
-1年11月30日
We examined loss of heterozygosity (LOH) at the retinoblastoma susceptibility gene (RB1) locus on chromosome 13q14 in 20 non-small-cell lung cancers (NSCLCs) using polymorphic markers. The expression of RB protein was examined by immunohistochemical analysis of paraffinembedded specimens of the same tumors. The results revealed that 10 of 16 informative cases showed an LOH at the RB1 locus, whereas only 2 of the 10 tumors lost expression of the RB protein. These 2 tumors had mutations in the remaining RB1 allele. Thus, inactivation of the RB1 gene appears to be involved in a small subset of NSCLCs only. To elucidate the presence of tumor-suppressor genes other than RB1 on 13q, heterozygosity at 15 different loci was investigated. Of 20 tumors analyzed, 15 showed an LOH at least at one locus, and the regions 13q12.1-qter, 13q12.2-14.2 and 13q14.1-q14.3, including the RB1 locus, were deleted in significant numbers of the tumors. Our results suggest that, in addition to the RB1 gene, abnormalities of other tumorsuppressor genes on chromosome 13q are involved in the development of human NSCLCs. Int. J. Cancer 74: 45-49.
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张学, Zhen-Ning Wang, Hui-Mian Xu, Li Jiang, Xin Zhou, Chong Lu, Xue Zhang
World J Gastroenterol 2004; 10 (21): 3094-3098,-0001,():
-1年11月30日
AIM: Survivin, a recently identified member of the inhibitor of apoptosis protein family, is expressed during development and in various human cancers. However, its expression in normal tissues and clinical relevance in cancers are still debated. In the present study, we analyzed the expression of the survivin gene in human primary and metastatic gastric cancer cells as well as in paired epithelial cells from normal gastric mucosa by means of a novel laser capture microdissection (LCM) technique coupled with reverse transcription-polymerase chain reaction (RT-PCR). METHODS: Thirty patients who had undergone gastrectomy with lymph node dissection for gastric cancer without preoperative treatments were included. Neoplastic tissue, metastatic lymph nodes, and apparently uninvolved normal tissue were collected from each patient. LCM-captured "pure" cell groups were espectively subjected to RT-PCR analysis with primers specific for the survivin gene. RESULTS: Of the paired samples from 30 gastric cancer patients studied, 24 (80%) primary gastric cancer cell groups and 7 (23%) adjacent morphologically "normal" gastric epithelial cell groups were shown to have a detectable survivin expression. There was a statistically significant difference in suvivin expression between these two groups (P<0.01). Meanwhile, 95% (19/20) of the metastatic gastric cancer cell groups from lymph nodes had a clear expression of the survivin gene. However, no significant correlation between survivin expression and clinicopathological features of gastric cancer was bserved in the present study.CONCLUSION: Survivin expression is present in the majority of gastric cancer cell groups obtained by LCM techniques. The high expression rate in metastatic lesions suggests a possible role of survivin in cancer invasiveness and metastasis. It may contribute to the detection of gastriccancer micrometastasis as a potential molecular marker. In addition, the high expression percentage renders survivin a potential target in the therapy for gastric cancer.
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【期刊论文】Expression of survivin mRNA in peritoneal lavage fluid from patients with gastric carcinoma
张学, WANG Zhen-ning, XU Hui-mian, JIANG Li, ZHOU Xin, LU Chong and ZHANG Xue
Chinese Medical Journal 2004; 117 (8): 1210-1217,-0001,():
-1年11月30日
Background Peritoneal dissemination is the most common pattern of metastasis in advanced gastric carcinoma with serosal invasion In the present study, we reported the clinical relevance of a new diagnostic method involving RT-PCR, using su rvivin as the target gene, for the detection of free cancer cells in peritoneal washes Methods Intraoperative peritoneal washes were obtained from 48 patients who underwent su rgery for gastric cancer RT-PCR analysis with primers specific for survivin and conventional cytological examinations were both performed Results Su rvivin mRNA was not detected in any peritoneal wash samples from patients with benign disease, but was detected in 28 of 48 samples taken from patients with gastric cancer and in all metastastic nodules Survivin expression in the peritoneal cavity significantly correlated with depth of cancer invasion, lymph node etastasis, and TNM stage There were 92% of clinically evident peritoneal metastasis cases showed detectable su rvivin expression The combination of survivin RT-PCR and cytological examination yielded positive results in 66 7% (32/48) of patients with gastric cancer, much higher than the results produced by cytological method alone Conclusions Survivin mRNA detected in peritoneal lavage fluid might indicate the presence of free cancer cells in the peritoneal cavity. The high sensitivity of the RT-PCR-based survivin assay suggests that su rvivin serves as a molecular marker for detecting peritoneal micrometastasis Its ubiquitous expression in peritoneal cancer cells and metastatic nodules also suggests a promising future therapeutic strategy based on su rvivin inhibition for cases of gastric cancer involving peritoneal metastasis
gastric carcinoma
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张学, 马中良, 杨怀义, 田波①
遗传学报,2003,30(7):693~696,-0001,():
-1年11月30日
真核生物中存在两种主要的非编码RNA(non-coding RNA),在真核生物中发挥重要作用。一类为微小RNA(microRNA,miRNA),另一为小干扰RNA(siRNA)。miRNA大小为119~25nt,在体内与蛋白质形成核糖核蛋白复合体(miRNA),在真核基因的表达调控,生长发育中起重要作用。siRNA在RNA干扰(RNA interference,RNAi)途径中起定位特异mRNA的作用。miRNA与siRNA有联系也有区别。miRNA在真核生物中的调控机制具有保守性。
真核生物, 微小C., U, 结合微小C., U 的核糖核蛋白复合体, C., U 干扰, 小干扰C., U
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张学
BioTechniques 29: 530-536 (September 2000),-0001,():
-1年11月30日
Current advances in biomolecular technology allow precise genetic fingerprinting of specific cells responsible for the pathogenesis of human diseases. This study demonstrates the feasibility of enerating target samples from laser capture microdissection (LCM) tissues suitable for hybridization of high-density oligonucleotide arrays for gene expression profiling. RNA was successfully isolated by LCM from three paired specimens of oral cancer and linearly amplified using T7 RNA polymerase. Evaluation of the cDNA revealed that five of five cellular maintenance transcripts are detected. Biotinylated cRNA was generated and hybridized to the human Test 1 GeneChip "probe arrays, which demonstrated that the RNA is of sufficient quality and integrity to warrant further analysis. Subsequent hybridization of the samples to the HuGenFL GeneChip probe arrays revealed that 26.5%-33.0% of the approximately 7000 represented genes are expressed in each of the six samples. These results demonstrate that LCM-generated tissues can generate sufficient quality cRNA for high-density oligonucleotide microarray analysis, an important step in determining comprehensive gene expression profiling using this high-throughput technology.hybridization of LCM-generated RNA to cDNA-based expression microarrays, no report has yet shown the successful hybridization to high-density oligonucleotide mircoarrays. The limited quantity and quality of RNA isolated using LCM continues to be a technical obstacle for in vivo analysis of gene expression using microarrays. While RNA isolated from LCM-harvested tissue can be converted into cDNA libraries, it is generally agreed that the most accurate representation of gene expression for DNA chips is achieved by making the target sample directly from the RNA or by a T7-based linear RNA amplification (2,4,5). Comprehensive gene expression analysis of LCM-isolated pure cell populations will represent a major biomedical advance in our understanding of the pathogenesis of human disease (7). A major challenge in this line of investigation is the ability to generate a sufficient amount and quality of the desireddesired macromolecule from biopsied material. The GeneChip"probe arrays (Affymetrix, Santa Clara, CA, USA) allow the generation of accurate and reproducible mRNA transcript-level data (3,6,9). The HuGeneFL probe array contains probes representing approximately 7000 full-length human genes. The ability to generate target samples from LCM-based cells and tissues for hybridization to DNA chips represents an important advance that demonstrates the feasibility of using this method of sample collection for gene expression analysis on DNA chips.
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【期刊论文】Interaction of the CDK2-associated protein-1, p12DOC-1=CDK2AP1, with its homolog, p14DOC-1R
张学, Waranun Buajeeb, a, c Xue Zhang, b, c Hiroe Ohyama, c David Han, c Rudee Surarit, * Yong Kim, c and David T.W. Wong c,
Biochemical and Biophysical Research Communications 315(2004)998-1003,-0001,():
-1年11月30日
Human DOC-1/CDK2AP1 gene encodes a growth suppressor protein of 12kDa (p12DOC-1=CDK2AP1). Recently, p12DOC-1=CDK2AP1 has been shown to associate with cell cycle proteins including CDK2 and DNA olymerase a/primase. It negatively regulates CDK2 activities and suppressesDNAreplication. Therefore, identification of other p12DOC-1=CDK2AP1 interacting proteins might clarify its role in the cell cycle regulation and carcinogenesis. The purpose of this study was to identify additional p12DOC-1=CDK2AP1 interacting proteins using the yeast two-hybrid system. Using human p12DOC-1=CDK2AP1 as a bait in a liver cDNA library screening, cDNA clones identical to human DOC-1R transcript were identified. The interaction between p12DOC-1=CDK2AP1 and p14DOC-1R was verified in vitro and in cells. GST pull-down assay and immunoprecipitation experiments confirmed the interaction between the two proteins. The ritical region for p12DOC-1=CDK2AP1's interaction with p14DOC-1R was defined to amino acids 20-25 by using a series of deletion mutants as baits in the yeast two-hybrid system. Our data indicated that p12DOC-1=CDK2AP1 could associate with its homologous protein, p14DOC-1R.
p12DOC-1=, CDK2AP1, p14DOC-1R, Yeast two-hybrid system, Cell cycle proteins
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张学, Hensin Tsao, , Xue Zhang, Eric Benoit and Frank G Haluska
Oncogene (1998) 16, 3397-3402,-0001,():
-1年11月30日
A novel tumor suppressor gene, PTEN/MMAC1, has been recently shown to be mutated in gliomas, breast, prostate, kidney cancers and melanomas. Loss-of-heterozygosity studies in melanoma have suggested the presence of at least one chromosome 10q locus lost early in tumor progression. In this study, we screened 45 melanoma cell lines and 17 paired uncultured metastatic melanoma and peripheral blood specimens for PTEN/MMAC1 alterations using PCR-SSCP and direct sequencing. We found nine melanoma cell lines with homozygous deletions (
cancer, genetics, mutation, PTEN/, MMAC1, melanoma
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【期刊论文】Identification and Mutation Analysis of DOC-1R, a DOC-1 Growth Suppressor-Related Gene
张学, Xue Zhang, *, † Hensin Tsao, ‡ Takanori Tsuji, § Shinsei inoshima, ¶ Jim McBride, § Paul Majewski, * Randy Todd, § obuyoshi Shimizu, ¶ David T. W. Wong, § David E. Housman, \ and Frank G. Haluska*,
Biochemical and Biophysical Research Communications 255, 59-63 (1999),-0001,():
-1年11月30日
The tumor suppressor gene MEN1 and several oncogenes including CCND1/cyclin D1/PRAD1 map to chromosome 11q13. However, molecular and cytogenetic analysis suggests the presence of a second tumor suppressor locus at this chromosome region. We have identified a novel gene from chromosome 11q13, which encodes a protein of 126 amino acids sharing an overall 57% identity with the p12DOC-1 protein encoded by the DOC-1 gene, the human homolog of hamster putative tumor suppressor doc-1 (deleted in oral cancer-1). We therefore designated the novel gene as DOC-1R for DOC-1-related. The cytogenetic location was con-firmed by chromosome fluorescent in situ hybridization. Northern blot analysis indicated that it was expressed in all the tissues examined. DOC-1R protein showed heterogeneous subcellular localization. RTPCR-SSCP analysis failed to detect deleterious mutations of the DOC-1R transcript in four premalignant oral keratinocyte lines and 20 different cancer cell lines from tumor types which frequently harbor LOH at chromosome 11q13.
tumor suppressor gene, mutation, DOC-1, DOC-1R.,
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