REGULATION OF AN EXTRACELLULAR XENOBIOTIC RESPONSE GENE

描述：（改编自研究者摘要） 组织承受损伤诱导的外源性物质的能力取决于 细胞合成保护和修复所需的新基因产物。 ApoJ，一种进化上保守的分泌性糖蛋白，能够结合 不同的疏水分子，已经被多个研究人员克隆 研究暴露于异生物质的组织中的新基因表达， 诱导损伤或凋亡。 有人提议， 在病理条件下的细胞保护，并强烈表达， 病变周围的细胞。 ApoJ也组成型表达， 在一系列有趣的上皮细胞中发育， 液体-组织边界的界面。 因此，apoJ是一种表达 在正常和病理生理的关键生物界面 情节 为了验证apoJ促进细胞外 损伤修复，研究人员建议将损伤修复的特征 apoJ基因敲除小鼠。 由于许多基因 通过外源性组织损伤激活，apoJ将作为一种理想的模型， 定义组织损伤诱导基因的机制。 第一特定 目的是检验apoJ在细胞凋亡中具有细胞保护功能的假设。 外源性组织损伤的部位。 要做到这一点，apoJ null 基因敲除和野生型小鼠耐受外源性组织损伤将 比较了 此外，apoJ在肾脏、脑和男性生殖系统中的作用也是研究的重点。 在三种不同的化学试剂诱导的两种损伤模型中， 评价组织特异性损伤和apoJ表达。 因为 它在许多组织中被各种各样的外源性物质诱导， 假设有一种共同的机制控制着基因的激活， 外源性损伤 为了验证这一假设，研究人员将使用 嵌合apoJ-CAT报告转基因以鉴定 apoJ基因负责激活三种损伤中的基因表达， 目标1中研究的模型。 如果相同的控制序列 负责每个组织对每个损伤的反应，这将 这表明apoJ基因可以作为鉴定的原型 新的和基本的损伤反应机制。 获得的消息 这些研究将明确apoJ在损伤反应中的重要性， 这可能是它与其他几种基因敲除结合的基础， 影响边界界面的损伤反应，并允许 识别允许细胞响应的重要遗传机制 和承受外源性物质的有害影响， 完整的动物

DESCRIPTION: (Adapted from the Investigator's Abstract) The ability of a tissue to withstand injury-inducing xenobiotics depends on the ability of cells to synthesize new gene products necessary for protection and repair. ApoJ, an evolutionarily conserved secretory glycoprotein capable of binding diverse hydrophobic molecules, has been cloned by multiple investigators studying new gene expression in tissues exposed to xenobiotic agents that induce injury or apoptosis. It has been proposed to play a role in cytoprotection during pathological conditions and is strongly expressed by cells that surround lesions. ApoJ is also expressed constitutively and developmentally in an interesting series of epithelial cells frequently at the interfaces of fluid-tissue boundaries. Thus, apoJ is a gene expressed at critical biological interfaces in both normal and pathophysiologic circumstances. To test the hypothesis that apoJ promotes extracellular injury repair, the investigators propose to characterize injury repair in apoJ-null knockout mice that they have generated. Since many genes are activated by xenobiotic tissue injury, apoJ will serve as an ideal model to define mechanisms for gene induction by tissue injury. The first specific aim will test the hypothesis that apoJ has a cytoprotective function at sites of xenobiotic tissue injury. To do this, the ability of apoJ null knock-out and wild type mice to withstand xenobiotic tissue injury will be compared. Additionally, apoJ's role in kidney, brain, and male reproductive tract injury models in which three different chemical agents induce both tissue specific injury and apoJ expression will be evaluated. Because of its inducibility in many tissues by a wide variety of xenobiotic agents, it is hypothesized that a common mechanism controls gene activation by xenobiotic injury. To test this hypothesis the investigators will use chimeric apoJ-CAT reporter transgenes to identify sequences and elements of the apoJ gene responsible for activating gene expression in the three injury models to be studied in aim 1. If the same control sequences are responsible for the responsiveness to each injury in each tissue, this will suggest that the apoJ gene can serve as a prototype for the identification of novel and fundamental injury response mechanisms. Knowledge gained from these studies will define the importance of apoJ in injury response, provide a foundation for its combination with several other gene knock-outs likely to affect injury response at boundary interfaces, and will allow the identification of important genetic mechanisms that allow cells to respond to and withstand injurious effects of xenobiotics in the context of the intact animal.