THE ROLE OF JAM-A IN CANCER METASTASIS AND SPERMATOGENESIS

这个子项目是许多研究子项目中利用 资源由NIH/NCRR资助的中心拨款提供。子项目和 调查员(PI)可能从NIH的另一个来源获得了主要资金， 并因此可以在其他清晰的条目中表示。列出的机构是 该中心不一定是调查人员的机构。 细胞-细胞连接在生理过程中很重要，紧密的连接有助于维持保护多细胞生物体免受环境影响的上皮细胞层。参与形成这些连接的细胞表面黏附蛋白在黏附丧失中发挥作用，这导致细胞变得迁移。我们已经鉴定并鉴定了一种新的细胞黏附分子，JAM-A，它表达于内皮细胞和上皮细胞的紧密连接。我们的结果表明，JAM-A与导致迁移行为的事件有关，包括癌细胞转移，以及不育症。1)乳腺癌细胞的转移行为与JAM-A的表达水平有关。我们将确定JAM-A在具有一定转移潜能的乳腺癌细胞系中的表达。我们将比较JAM-A的表达与转移潜能，并使用细胞和小鼠模型来证实两者之间的关系。2)JAM-A的翻译后修饰影响乳腺癌细胞的转移能力。我们将确定JAM-A的翻译后修饰是否与这些细胞的转移行为有关。同样，我们将利用体外和体内的肿瘤转移模型。3)JAM-A信号转导调节乳腺癌细胞的转移潜能。通过JAM-A诱导的细胞内信号通路将被描述。4)JAM-A的表达减少和/或翻译后修饰影响支持细胞紧密连接，导致精子发生异常。我们将对JAM-A WT和K/O小鼠睾丸的Sertoli-Sertoli紧密连接动力学和后者的睾丸组织学进行特征描述，然后利用Sertoli细胞特异性启动子驱动JAM-A转基因表达来进行JAM-A K/O小鼠受精的转基因挽救。我们的结果将有助于确定JAM-A在癌细胞转移和男性亚生育中的作用，并可以确定治疗靶点。

This subproject is one of many research subprojects utilizing the resources provided by a Center grant funded by NIH/NCRR. The subproject and investigator (PI) may have received primary funding from another NIH source, and thus could be represented in other CRISP entries. The institution listed is for the Center, which is not necessarily the institution for the investigator. Cell-cell junctions are important in physiological processes, with tight junctions helping to maintain the epithelial cell layer that protects multicellular organisms from the environment. Cell surface adhesion proteins involved in forming these junctions play a role in the loss of attachment, which leads cells to become migratory. We have identified and characterized a novel cell adhesion molecule, Junctional Adhesion Molecule-A (JAM-A), which is expressed at endothelial and epithelial cell tight junctions. Our results implicate JAM-A in the events leading to migratory behavior, including cancer cell metastasis, as well as in subfertility. We therefore propose to test the following hypotheses in this proposal: 1) Metastatic behavior of breast cancer cells is related to the expression level of JAM-A. We will determine the expression of JAM-A in breast cancer cell lines with a range of metastatic potentials. We will compare the expression of JAM-A to the metastatic potential, and use cellular and mouse models to confirm the relationship. 2) Post-translational modifications of JAM-A influence the metastatic ability of breast cancer cells. We will determine if post-translational modification of JAM-A is related to the metastatic behavior of these cells. Again we will utilize in vitro, as well as in vivo, models of tumor metastasis. 3) Signaling through JAM-A regulates the metastatic potential of breast cancer cells. The intracellular signaling pathway induced through JAM-A will be characterized. 4) Reduced expression and/or post-translational modification of JAM-A affect Sertoli cell tight junctions, leading to abnormal spermatogenesis. We will characterize the Sertoli-Sertoli tight junction dynamics in the testis of JAM-A WT and K/O mice, and the testicular histology in the latter, and then perform a transgenic rescue of the subfertility in JAM-A K/O mice using a Sertoli-cell specific promoter to drive the expression of a JAM-A transgene. Our results will help define the role of JAM-A in cancer cell metastasis and male subfertility, and can identify therapeutic targets.