张幼怡
一直从事肾上腺素受体与心血管疾病发病机制的研究。
个性化签名
- 姓名:张幼怡
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学术头衔:
博士生导师,
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学科领域:
内科学
- 研究兴趣:一直从事肾上腺素受体与心血管疾病发病机制的研究。
张幼怡现任中国病理生理学会心血管专业委员会主任委员,中国病理生理学会受体专业委员会副主任委员,中国药理学会心血管药理专业委员会委员。《中国分子心脏病学杂志》、《中国药理与毒理》、《生理学报》编委。获国家教委中国高校自然科学一等奖(第2完成人),作为项目主持者或主要完成者,先后承担10项各级科学基金课题,包括:国家科技部重点基础研究发展规划项目“973”子项目1项;国家自然科学基金4项,等。发表科研论文90余篇。以第一作者发表论文18篇,以责任作者发表论文22篇,其中SCI收录30余篇,参与编写《动态心电图》,《分子核医学》和《受体信号转导系统与疾病》著作。从1992年起一直从事肾上腺素受体与心血管疾病发病机制的研究, 特别是肾上腺素受体在心血管系统的分布,信号转导, 生理功能及在病理状态下的改变和受体之间的交互作用的研究。近年开始研究肾上腺素受体在细胞内的转运和心血管再塑时肾上腺素受体在基因水平的调控整合。在长期的研究工作中,采用药理学、生理学、病生理学、细胞生物学、分子生物学等研究方法,在整体、细胞和分子水平研究了多种亚型肾上腺素受体在心血管系统的分布、功能、信号传导机制和相互之间的交互作用以及激动剂作用下的调节以及在疾病状态下的改变等方面,对多种亚型肾上腺素受体在心血管共存的生理与病理意义进行了系统的研究。近年建立了基因芯片检测平台和酵母双杂交方法,采用高通量的基因芯片技术,主要研究了不同心肌重塑状态下基因表达谱的特征性改变,以及药物干预引起的相应变化,同时对基因群进行了初步的表达行为聚类分析和相互关系网络结构分析。采用酵母双杂交技术,发现新的与肾上腺素受体结合调节蛋白。
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10
张幼怡, Zhenzhong Li, Youyi Zhang, Daqing Li, and Yue Feng
The Journal of Neuroscience, July 1, 2000, 20 (12): 4944-4953,-0001,():
-1年11月30日
Quakingviable (qkv) is a well known dysmyelination mutation. Recently, the genetic lesion of qkv has been defined as a deletion 5' to the qkI gene, which results in the severe reduction of the qkI-encoded QKI RNA-binding proteins in myelinproducing cells. However, no comprehensive model has been proposed regarding how the lack of QKI leads to dysmyelination. We hypothesized that QKI binds to myelin protein mRNAs, and the lack of QKI causes posttranscriptional misregulation, which in turn leads to the loss of the corresponding myelin proteins. To test this hypothesis, we developed an Rnase protection assay to directly measure the mRNA isoforms encoding the myelin basic proteins (MBPs) in the brain. Our result suggested that isoform-preferential destabilization of MBP mRNAs in the cytoplasm was responsible for the reduced MBPs in the qkv/qkv brain during early myelination. In addition, we detected markedly reduced MBP mRNAs in the qkv/qkv myelin fraction with concomitant accumulation of MBP mRNAs associated with membrane-free polyribosomes. Presumably, the impaired localization of MBP mRNAs to the myelin membrane may cause insufficient incorporation of the newly synthesized MBPs into the myelin sheath. Finally, we observed interactions between QKI and MBP mRNAs, and removing MBP 39UTR significantly reduced QKI-binding. Taken together, these observations suggest that misregulation at multiple posttranscriptional steps is responsible for the severe reduction of MBPs in qkv dysmyelination, presumably because of the lack of interactions between MBP mRNAs and the QKI RNA-binding proteins.
myelination, myelin basic protein, mRNA degradation and localization, quakingviable, signal transduction activators of RNA, posttrans, c, r, i, p, t, ional regulation
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【期刊论文】Tyrosine phosphorylation of QKI mediates developmental signals to regulate mRNA metabolism
张幼怡, Youyi Zhang, Zifan Lu, Li Ku, Yuntao Chen, Houping Wang and Yue Feng
The EMBO Journal Vol. 22 No. 8 pp. 1801-1810, 2003,-0001,():
-1年11月30日
The selective RNA-binding protein QKI is essential for myelination in the central nervous system (CNS). QKI belongs to the family of signal transduction activators of RNA (STARs), characteristic of binding RNA and signaling molecules, therefore is postulated to regulate RNA homeostasis in response to developmental signals. Here we report that QKI acts downstream of the Src family protein tyrosine kinases (Src-PTKs) during CNS myelination. QKI selectively interacted with the mRNA encoding the myelin basic protein (MBP). Such interaction stabilized MBP mRNA and was required for the rapid accumulation of MBP mRNA during active myelinogenesis. We found that the interaction between QKI and MBP mRNA was negatively regulated by Src-PTK-dependent phosphorylation of QKI. During early myelin development, tyrosine phosphorylation of QKI in the developing myelin drastically declined, presumably leading to enhanced interactions between QKI and MBP mRNA, which was associated with the rapid accumulation of MBP mRNA and accelerated myelin production. Therefore, developmental regulation of Src-PTK-dependent tyrosine phosphorylation of QKI suggests a novel mechanism for accelerating CNS myelinogenesis via regulating mRNA metabolism.
mRNA metabolism, myelin development, RNA-binding protein, Src family protein tyrosine kinases, tyrosine phosphorylation
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张幼怡, P. Li, J. Li, X. Feng, Z. Li, R. Hou, C. Han, Y. Zhang*
CMLS, Cell. Mol. Life Set. 60(2003)2200-2209,-0001,():
-1年11月30日
Catecholamines play an important role in the development of cardiac hypertrophy. To observe car diomyocyte specific gene expression changes induced by catecholamines in vivo, left ventricular cardiomyocytes were isolated from male Sprague-Dawley rats after continuous infusion of norepinephrine (NE; 0.2mg/kg per hour intravenously) for 0.5, 1, 2, 3 and 7 days The gene expression profiles of these cells during different NE infusion stages were assessed by using a cDNA microarray, and the microarray data were further analyzed by a clustering method. Cardiac hypertrophy was induced upon continuous NE infusion, with the peak at 3 days. Meanwhile, manifest changes in gene expression profile within cardiomyocytes over the time course were revealed, most of the genes never having been reported to be involved in cardiac hypertrophy. The number of genes displaying differential expression also peaked at the middle stage of infusion (2-3 days), and the majority of the signaling molecules were found differentially expressed mainly at this stage, including phosphatidylinositol 3-kinase, calcium/calmodulin-dependent protein kinase II and non-receptor tyrosine kinases, etc. The tumor suppressor p53 was found up-regulated at very early (0.5 days) and late stages (7 days) of NE infusion. Self-organization clustering analysis revealed subsets of coordinate regulated genes. One set consisted of several enzymes involved in energy metabolism, including carnitine octanoyltransferase, ATP synthase subunit c, pancreatic lipase and glycogen phosphorylase, possessing a similar expression pattern with a rapidly elevated expression level at the early stage of NE infusion. This is the first study to provide transcriptional information for cardiomyocytes, a single cell type, in the heart during the development of cardiac hypertrophy in vivo, and may provide accurate clues to elaborate hypotheses about the evolution of this pathology.
Myocyte, cardiac, hypertrophy, norepinephrine, gene expression profile
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【期刊论文】α1A-肾上腺素受体与骨形成蛋白-1片段在人胚肾293细胞中的结合
张幼怡, 徐琦, 张坦, 韩启德, 张幼怡*
生理学报,2003,55(6):692~698,-0001,():
-1年11月30日
用酵母双杂交方法发现骨形成蛋白-1(bone morphogenetic pmtein-1, BMP-1)的片段可以与α1A-肾上腺素受体(adrenergic receptor, AR)的细胞内游离C末端结合。进一步探讨了二者在哺乳动物表达系统人胚肾293细胞(human embryonic cell 793, HEK293)中的相互作用。采用PCR方法构建含BMP-1片段cDNA的真核表达质粒PCP3HA,将其与含水量生和人α1A-AR cDNA的质粒PUT-α1A分别或共同转染HEK293细胞,用免疫印迹法检测到α1A-AR和BMP-1在HED293细胞有相应的蛋白表达。用酶联免疫吸附实验对免疫印迹鉴实过的细胞裂解液进行检测,观察到空白对照组,单独转染PDT-α1A和单独转染PCP3HA的细胞、OD490值分别为0.034±0.027、0.042±0.019、0.030±0.0096,三者之间无显著性差异。共转染PDT-α1A或PCT3HA的细胞,OD490值为0.57±0.12,较其实三组其有显著性差异(均P<0.001)。免疫共沉淀结果显示,单独转染PDT-α1A或PCP3HA的细胞,免疫沉淀产物中均不能检测到BMP-1片段,只有共转染PDT-α1A和PCP3HA的细胞,在其免疫产物中能检测到BMP-1片段。ELISA和免疫沉淀淀结果均表明α1A-AR与BMP-1的片段在HEK293细胞中存在蛋白水平的相互作用。
α1A-肾上腺素受体, 骨形成蛋白-1, 酶联免疫吸附实验
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张幼怡, SONG Yao, HUANG Yan, DONG Er-Dan, HAN Qi-De, ZHANG You-Yi
Song Y et al/Acta Pharmacol Sin 2003 Jun; 24 (6): 549-554,-0001,():
-1年11月30日
AIM: To investigate the characterization of cAMP response mediated by α1-adrenoceptor (α1-AR) subtypes in HEK293 cells. METHODS: (1) Full-length cDNA encoding three α1-AR subtypes were transfected into HEK293 cells by the calcium phosphate precipitation method, respectively. (2) The densities of α1-AR subtypes expressed in HEK293 cells were measured by radioligand binding assay. (3) cAMP accumulation was measured by [3H] adenine prelabeling method. RESULTS: (1) Activation of each of three subtypes resulted in an increase of cAMP accumulation in HEK293 cells in a dose-dependent manner, which was inhibited by selective α1-AR antagonist prazosin. (2) Comparing the pharmacological property, the maximal responses of α1A-AR to agonists were the most potent, while the sensitivity of α1-AR subtypes to norepinephrine (NE) was the highest. CONCLUSION: Each of three α1-AR subtypes can mediate cAMP accumulation in HEK293 cell line, and there are differences in pharmacological property.
alpha-1 adrenergic receptors, cyclic AMP, HEK293 cells, radioligand assay
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【期刊论文】异丙肾上腺素对小鼠心肌MAPK、NFκKB和JAK/STAT信号转导途径的激活效应
张幼怡, 尹峰, 朱昀, 李平, 韩启德, 张幼怡*
生理学报,2003,55(4):449~453,-0001,():
-1年11月30日
为研究异丙肾上腺素(isoproterenol, ISO)诱导心肌肥厚或心肌重塑的分子机制,本工作以成年雄性Balb/e小鼠为研究对象,通过腹腔注射ISO,采用蛋白免疫印迹杂交方法观察ISO对小鼠心肌丝裂素活化蛋白激酶(mitogen-activted protein kinase, MAPK)、核因子-κB(NFκB)和Janus激酶/信号转导因子和转录激活因子(JAK/STAT)途径的激活效应。结果发现,ISO腹腔注射后可早期(5min)激活心肌MAPK(ER1/2和p38);ISO对心肌NFκB的激活效应表现为双相性,激活高峰分别为5和120min;ISO腹腔注射60min后可显著促进STAT3的酪氨酸磷酸化,6h时基本恢复到基础水平。上述结果提示,ISO对多种细胞内信号转导途径均具有激活效应,但表现出明显的时相差异。探明这些信号转导途径的时空整合规律,将有助于深化对心肌重塑发生机制的认识。
异丙肾上腺素, 心肌, 丝裂素活化蛋白激酶, 核因子-κB, Janus激酶/, 信号转导因子和转录激活因子
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张幼怡, 李平*, 李劲梁*, 尹峰, 闫洁, 冯新恒, 李昭屏, 韩启德, 张幼怡**
生理学报,2003,55(3):334~335,-0001,():
-1年11月30日
为观察大鼠心肌重塑过程中Axin蛋白质表达水平的变化,实验用颈静脉输注去甲肾上腺素(NE)和动静脉造瘘(AVF)方法复制大鼠心肌重塑病理模型,采用超声心动术检测心脏结构和收缩功能。取病理模型大鼠左心室以及分离培养的成年大鼠心肌成纤维细胞,采用Westrn blot技术检测Axin蛋白质的表达水平。结果观察到,在颈静脉输注NE3d后,大鼠心脏发生向心性心肌肥厚和心肌纤维化,其左心室的Axin蛋白表达水平较对照组显著升高。A-V造瘘术一周后引起大鼠离心性心肌肥厚,心肌无明显纤维化,心肌Axin表达量与对照相比无显著变化。在分离培养的成年大鼠心肌成纤维细胞,NE处理24h能明显升高Axin蛋白的表达水平。上述结果表明,大鼠心脏有Axin蛋白质表达,NE致大鼠心肌重塑过程中Axin蛋白表达显著增加,可能与该过程的心肌纤维化有关。
病理学, 心肌重塑, 去甲肾上腺素, 纤维化
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【期刊论文】β2-肾上腺素受体在新生大鼠心肌成纤维细胞中的分布及其促增殖作用
张幼怡, 尹峰, 吕志珍, 韩启德, 张幼怡*
生理学报,2003,55(3):251~254,-0001,():
-1年11月30日
为了明确β-肾上腺素受体(AR)亚型在新生大鼠心肌成纤维细胞中的分布及其在成纤维细胞增殖反应中的作用,采用放射配体结合实验和[3H]-thymidine掺入法检测了新生大鼠心肌成纤维细胞的β-AR密度和DNA合成速率。结果显示,在培养心肌细胞和心肌成纤维细胞中β-AR密度(Bmax)和解离常数(KD)无显著性差异;竞争抑制曲线分析结果提示,心肌成纤维细胞对CGP 20712A和ICI 118551单位点拟合均显著优于两位点拟合(P<0.01),表现为对选择性β1-AR拮抗剂CGP 20712A的低亲和性(IC50值:10.1μmol/L)和对选择性β2-AR拮抗剂ICI 118551的高亲和性(IC50值:0.147μmol/L)。异丙肾上腺素(ISO)促心肌成纤维细胞增殖作用可被ICI 118551和心得安(非选择性β-AR拮抗剂)完全抑制,而CGP 20712A则无此作用。上述结果提示,在培养心肌成纤维细胞中β2-AR亚型占绝对优势,并且ISO引起的心肌成纤维细胞增殖反应是由β2-AR介导的。
β-肾上腺素受体, 放射配体结合实验, 心肌成纤维细胞, 增殖
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张幼怡, 李平*, 李劲梁*, 候嵘, 韩启德, 张幼怡**
生理学报,2003,55(2):191~196,-0001,():
-1年11月30日
为观察大鼠发育成熟过程中心脏生长与其基因表达谱变化的关系,应用超声心动术检测8、10、12周龄Wistar大鼠的心脏结构和功能指标,应用cDNA基因芯片技术观察心脏基因表达水平的变化。大鼠从8周龄生长至12周龄,体重增加约45.7%(287±13g vs 197±10g),前2周和后2周增加幅度相近。心脏左心室重量和室壁厚度分别增加约27.7%(0.60±0.03g vs 0.47±0.02g)和23.6%(2.04±0.04mm vs 1.65±0.13mm)前2周增加幅度明显大于后2周。基因表达谱的改变涉及细胞结构、代谢、氧化应激及信号转导等多方面的基因。10周龄和8周龄大鼠比较,变化的基因多数上调;12周龄和10周龄大鼠比较,基因表达谱基本又返转至8周龄水平。结果表明,大鼠在成长期的4周内(8-12周龄),左心室基因表达谱发生的变化适应生理性心肌生长需要。
生理学, 基因表达, 基因芯片, 心脏, 生长
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张幼怡, 徐琦, 朱卫忠, 吕志珍, 张幼怡**, 韩启德
中国科学(C辑),2003,33(2):133~138,-0001,():
-1年11月30日
采用大鼠整体灌流模型,同时测定灌流大鼠后肢血管床灌流压和全身平均动脉压,通过动态观察,比较多种α1-肾上腺素受体(α1-AR)亚型选择性拮抗剂对两者影响的异同,初步探讨α1-AR 亚型在大鼠整体血压调节中的作用。结果表明:α1-AR 选择性拮抗剂(prazosin 组13.5±3.6 vs 15.1±4.3,n=11)和α1A-AR 亚型选择性拮抗剂(5-methyl-urapidil组2.4±0.9 vs 3.7±2.3,n=12;RS-17053 组3.2±1.6 vs 4.4±3.3,n=12)均对正常大鼠苯肾上腺素引起后肢血管床升压反应曲线和平均动脉压升压反应曲线的右移程度(dose ratio,Dr)无明显影响,α1D-AR 亚型选择性拮抗剂(BMY 7378 组1.9±0.9 vs 2.2±0.8,n=8)对正常大鼠两者苯肾上腺素加压反应也无差别;自发性高血压大鼠(RS-17053 组3.4±0.6 vs 4.3±0.9,n=5;BMY 7378 组1.7±0.5 vs 1.7±0.5,n=8)的反应同正常大鼠相似。提示介导苯肾上腺素引起麻醉大鼠全身动脉加压效应的α1-AR与引起大鼠后肢血管床收缩的α1-AR可能是同一种亚型,即α1A-AR。
α1-肾上腺素受体 血压 拮抗剂 自发性高血压大鼠
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