Eph Kinase Signaling In Renal Epithelial Cells

肾上皮细胞中的 Eph 激酶信号传导

• 批准号: 8091272
• 负责人: Bingcheng Wang
• 金额: $ 32.18万
• 依托单位: CASE WESTERN RESERVE UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2008
• 资助国家: 美国
• 起止时间: 2008-06-01 至 2014-05-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8091272
• 关键词: 3-Dimensional; Adherens Junction; Affect; Behavior Therapy; Binding; Biological; Biological Models; Biological Process; Breeding; Cadherins; Cardiovascular system; Cell Adhesion; Cell Differentiation process; Cell Migration Inhibition function; Cell Separation; Cell membrane; Cell physiology; Cell-Cell Adhesion; Cells; Collagen; Congenital Abnormality; Cues; Defect; Development; Developmental Process; E-Cadherin; Embryo; End stage renal failure; Ephrin-A1; Ephrins; Epithelial; Epithelial Cells; Event; Gel; Goals; Growth; Health; Hepatocyte Growth Factor; Human Genome; Hypertension; In Vitro; Individual; Invaded; Kidney; Kidney Diseases; Knock-out; Knockout Mice; Lead; Life; Ligands; Link; Lung; MDCK cell; Maintenance; Mammary gland; Mediating; Medical; Membrane; Mesenchyme; Metanephric Diverticulum; Molecular; Molecular Profiling; Morphogenesis; Mus; Nephrons; Organ; Organism; Pattern; Phosphotransferases; Prostate; Protein Dephosphorylation; Protein Tyrosine Phosphatase; Publishing; Receptor Protein-Tyrosine Kinases; Regulation; Reporting; Role; Signal Pathway; Signal Transduction; Structure of mesonephric duct; System; Testing; Tissues; Tyrosine Phosphorylation; Ureter; base; body system; cell behavior; cell growth; cell motility; fascinate; in vivo; in vivo Model; insight; kidney cell; member; nephrogenesis; nervous system development; novel; plakoglobin; response; selective expression; spatiotemporal

DESCRIPTION (provided by applicant): The 14 members of Eph kinases constitute the largest subfamily of receptor tyrosine kinases in mammalian system and bind membrane-anchored ligands called ephrins. The pivotal role of Eph/ephrin interactions in regulating development of nervous and cardiovascular systems is well substantiated. However, whether they also epithelial development remains largely unexplored. The published and preliminary results by the applicant show that Eph kinases are novel regulators of epithelial branching morphogenesis. In MDCK renal epithelial cells, ligand activation of endogenous EphA2 potently inhibited HGF/SF-induced branching morphogenesis in 3-D collagen gels. In embryonic kidneys in vivo, EphA2 was selectively expressed in ureteric bud (UB), while ephrin-A1 was preferentially expressed in surrounding metanephric mesenchyme (MM). We hypothesize that the localized Eph/ephrin interactions UB/MM boundary allows contact-dependent guidance of renal branching morphogenesis. Supporting this hypothesis, kidneys from EphA2 knockout mice showed abnormal branching morphogenesis. The goal of this proposal is to take advantage of the unique model systems that we have established to determine the cellular and molecular bases underlying Eph kinase regulation of kidney development. In Aim 1, we will establish spatiotemporal expression profiles of all major EphA kinases and ephrin-As during metanephric kidney development. In Aim 2, we will focus on how perturbations of EphA/ephrin-A interactions will affect renal morphogenesis in vivo, by creating EphA1/EphA2 compound knockout. Specific Aim 3, we will use renal epithelial cell in vitro to gain insights on how EphA kinases regulate E-cadherin-mediated cell-cell adhesion and signaling. Completion of this proposal will fill a gap in our understanding on the role of Eph-ephrin interactions in the development metanephric kidney. Understanding mechanisms of UB branching morphogenesis has not only developmental significance, but also medical importance. Abnormal branching morphogenesis can lead to renal agenesis and malpositioning or duplication of the ureter, which are common birth defects. More subtle defects in UB growth and branching may result in reduced nephron number, which may predispose individuals to renal diseases later in life, including hypertension. The proposed studies can potentially lead to a new way to modulate kidney cell behaviors for the treatment of kidney diseases.Completion of this proposal will fill a gap in our understanding on the role of Eph-ephrin interactions in the development of the kidney. Understanding mechanisms of UB branching morphogenesis has not only developmental significance, but also medical importance. Abnormal branching morphogenesis can lead to renal agenesis and malpositioning or duplication of the ureter, which are common birth defects. More subtle defects in UB growth and branching may result in reduced nephron number, which may predispose individuals to renal diseases later in life, including hypertension and end stage renal disease. The proposed studies can potentially lead to a new way to modulate kidney cell behaviors for the treatment of kidney diseases. PUBLIC HEALTH RELEVANCE: Completion of this proposal will fill a gap in our understanding on the role of Eph-ephrin interactions in the development of the kidney. Understanding mechanisms of UB branching morphogenesis has not only developmental significance, but also medical importance. Abnormal branching morphogenesis can lead to renal agenesis and malpositioning or duplication of the ureter, which are common birth defects. More subtle defects in UB growth and branching may result in reduced nephron number, which may predispose individuals to renal diseases later in life, including hypertension and end stage renal disease. The proposed studies can potentially lead to a new way to modulate kidney cell behaviors for the treatment of kidney diseases.

描述（由申请人提供）：EPH激酶的14个成员构成了哺乳动物系统中受体酪氨酸激酶最大的亚家族，并结合称为Ephrins的膜锚定的配体。 EPH/Ephrin相互作用在调节神经和心血管系统发展中的关键作用得到了充分证实。但是，它们是否也基本上没有探索上皮发展。申请人发表的初步结果表明，EPH激酶是上皮分支形态发生的新型调节剂。在MDCK肾上皮细胞中，内源性EPHA2的配体激活有效抑制3-D胶原蛋白凝胶中HGF/SF诱导的分支形态发生。在体内的胚胎肾脏中，在输尿管芽（UB）中选择性表达Epha2，而Ephrin-A1优先表达在周围的元素间质（MM）中。我们假设局部的EPH/Ephrin相互作用UB/MM边界允许接触依赖于肾脏分支形态发生的指导。支持这一假设，来自Epha2基因敲除小鼠的肾脏表现出异常的分支形态发生。该提案的目的是利用我们建立的独特模型系统来确定肾脏发育的EPH激酶调节的细胞和分子碱基。在AIM 1中，我们将在跨肾脏肾脏发育过程中建立所有主要的Epha激酶和Ephrin-AS的时空表达谱。在AIM 2中，我们将重点关注Epha/Ephrin-A相互作用的扰动如何通过创建EPHA1/EPHA2化合物敲除体内影响体内肾脏形态发生。具体的目标3，我们将在体外使用肾上皮细胞，以了解Epha激酶如何调节E-cadherin介导的细胞粘附和信号传导。该提案的完成将填补我们对Eph-ephrin相互作用在发育肾上腺肾脏中的作用的理解的空白。了解UB分支形态发生的机制不仅具有发育意义，而且具有医学意义。异常的分支形态发生会导致输尿管的肾脏发育不全或重复，这是常见的先天缺陷。 UB生长和分支的更细微的缺陷可能导致肾单位数量减少，这可能会使个体易患肾脏疾病，包括高血压。拟议的研究可能会导致一种新的方法来调节肾脏细胞行为以治疗肾脏疾病。该提案的全面将填补我们对以弗所蛋白相互作用在肾脏发展中的作用的差距。了解UB分支形态发生的机制不仅具有发育意义，而且具有医学意义。异常的分支形态发生会导致输尿管的肾脏发育不全或重复，这是常见的先天缺陷。 UB生长和分支的更细微的缺陷可能导致肾单位数量减少，这可能会使个体在以后的生活中，包括高血压和末期肾脏疾病。拟议的研究可能会导致一种调节肾细胞行为以治疗肾脏疾病的新方法。公共卫生相关性：该提案的完成将填补我们对弗氏蛋白相互作用在肾脏发展中的作用的差距。了解UB分支形态发生的机制不仅具有发育意义，而且具有医学意义。异常的分支形态发生会导致输尿管的肾脏发育不全或重复，这是常见的先天缺陷。 UB生长和分支的更细微的缺陷可能导致肾单位数量减少，这可能会使个体在以后的生活中，包括高血压和末期肾脏疾病。拟议的研究可能会导致一种调节肾细胞行为以治疗肾脏疾病的新方法。

项目成果

A small molecule agonist of EphA2 receptor tyrosine kinase inhibits tumor cell migration in vitro and prostate cancer metastasis in vivo.

• DOI: 10.1371/journal.pone.0042120
• 发表时间: 2012
• 期刊: PloS one
• 影响因子: 3.7
• 作者: Petty A;Myshkin E;Qin H;Guo H;Miao H;Tochtrop GP;Hsieh JT;Page P;Liu L;Lindner DJ;Acharya C;MacKerell AD Jr;Ficker E;Song J;Wang B
• 通讯作者: Wang B

EphA receptor signaling--complexity and emerging themes.

• DOI: 10.1016/j.semcdb.2011.10.013
• 发表时间: 2012-02
• 期刊: SEMINARS IN CELL & DEVELOPMENTAL BIOLOGY
• 影响因子: 7.3
• 作者: Miao, Hui;Wang, Bingcheng
• 通讯作者: Wang, Bingcheng

Cancer cells exploit the Eph-ephrin system to promote invasion and metastasis: tales of unwitting partners.

• DOI: 10.1126/scisignal.2002153
• 发表时间: 2011-05-31
• 期刊: Science signaling
• 影响因子: 7.3
• 作者: Wang B

Radio-deoxynucleoside Analogs used for Imaging tk Expression in a Transgenic Mouse Model of Induced Hepatocellular Carcinoma.

用于对诱导性肝细胞癌转基因小鼠模型中的 tk 表达进行成像的放射性脱氧核苷类似物。

• DOI: 10.7150/thno.3371
• 发表时间: 2012
• 期刊: Theranostics
• 影响因子: 12.4
• 作者: Tian,Haibin;Lu,Xincheng;Guo,Hong;Corn,David;Molter,Joseph;Wang,Bingcheng;Luo,Guangbin;Lee,Zhenghong
• 通讯作者: Lee,Zhenghong