REGULATION OF AN EXTRACELLULAR XENOBIOTIC RESPONSE GENE

描述：(改编自《调查者摘要》) 组织对外源致伤物质的耐受能力取决于 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型糖蛋白 多种疏水分子，已被多名研究人员克隆 研究暴露于外源药物的组织中新的基因表达 诱导损伤或细胞凋亡。有人提议发挥作用，在 在病理条件下的细胞保护，并强烈表达 病变周围的细胞。ApoJ也是根据宪法表达的，并且 在一系列有趣的上皮细胞中发育，通常在 液体-组织边界的界面。因此，apoJ是一个表达的基因 在正常和病理生理学的关键生物学界面上 情况。为了检验apoJ促进细胞外的假设 损伤修复，研究人员建议将损伤修复描述为 他们产生的apoJ-空基因敲除小鼠。因为很多基因都是 由异种组织损伤激活的apoJ将成为理想的模型 定义由组织损伤引起的基因诱导机制。第一个具体 AIM将检验载脂蛋白J具有细胞保护功能的假设 异种组织损伤的部位。为此，apoJ NULL的能力 基因敲除和野生型小鼠将承受异种组织损伤 比较一下。此外，载脂蛋白J在肾脏、脑和男性生殖中的作用 三种不同化学制剂诱导的肠道损伤模型 将评估组织特异性损伤和apoJ的表达。因为. 它在许多组织中都可以被各种异源物质诱导，它 假设有一种共同的机制通过 异种生物损伤。为了验证这一假设，研究人员将使用 嵌合ApoJ-CAT报告基因用于鉴定ApoJ-CAT的序列和元件 在三种损伤中负责激活基因表达的apoJ基因 目标1中要研究的模型。如果相同的控制序列 负责对每个组织中的每个损伤的反应，这将 提示apoJ基因可以作为鉴定的原型。 新的和基本的伤害反应机制。从以下方面获得的知识 这些研究将确定载脂蛋白J在损伤反应中的重要性，提供 它可能与其他几个基因敲除相结合的基础 影响边界界面的伤害反应，并将允许 识别允许细胞作出反应的重要遗传机制 在下列情况下防止和抵御外来生物的有害影响 完好无损的动物。

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.