GENETIC REGULATION OF THE HEPATIC ACUTE-PHASE RESPONSE

控制基因表达的分子机制在 进化，导致物种特定变化的出现 在基因调控模式中。对这些修改的分析提供了 对分子作用本质和机制的新见解 决定基因活性的元素，也是基因的主要靶点 进化的过程。为了解决这个问题，我们开发了 以小鼠急性时相蛋白基因为模型。这些基因编码了 肝脏分泌的许多血浆蛋白是协调的 在急性炎症期间诱导的；诱导是由 几种激素的联合作用，包括白细胞介素1， 白介素6和糖皮质激素。重要的是，它的结构和 急性期基因的表达表现出广泛的差异 老鼠物种。此外，虽然肝脏基因的总体谱 对急性期的反应在哺乳动物物种中是保守的， 包括老鼠在内，这些基因做出反应的确切机制是 不。在这次续签申请中，我们建议继续分子 急性时相蛋白基因种间变异的遗传分析 调节，侧重于α(1)-酸的两个多基因系统 糖蛋白(AGP)和α(1)-抗胰蛋白酶(AT)在 在系统发育上具有代表性的三种小鼠：家鼠M、家鼠M Caroli和M saxicola。主要感兴趣的具体问题包括： AGP基因簇中的激素调节元件是如何 重新安排，以及在MU中演变了哪些新的响应元素 与大鼠的单基因复制系统相比，物种？什么是 导致肾脏异常的调节因素的性质 AT基因在M caroli和M saxicola中的表达及其调控 不同基因在正常肝脏中的表达 生理和压力状态？我们的根本目标是定义和 描述顺式和反式作用因素对 基因表达表型的进化衍生的改变。我们的 努力将提供有关分子机制的新信息 控制哺乳动物的急性时相反应及其进化； 信息将大大增加我们对基因的一般了解 哺乳动物肝脏中的转录及其调控。

The molecular machinery for control of gene expression is modified during evolution, resulting in the appearance of species-specific alterations in gene regulatory patterns. Analysis of these modifications provides novel insights into the nature and mechanisms of action of molecular elements that determine gene activity and that are primary targets for the evolutionary process. To address this issue, we have developed the acute phase protein genes of mice as a model. These genes, which encode a number of plasma proteins secreted by the liver are coordinately induced during an acute inflammation; induction is mediated by the combined action of several hormones, including interleukin-1, interleukin-6, and glucocorticoids. Importantly, the structure and expression of the acute phase genes exhibit extensive variation among mouse species. In addition, while the overall spectrum of hepatic genes responding to an acute phase is conserved among mammalian species, including mice, the exact mechanisms by which these genes respond are not. In this renewal application, we propose to continue the molecular genetic analysis of interspecies variations in acute phase protein gene regulation, focusing on the two multi-gene system of alpha(1)-acid glycoprotein (AGP), and alpha(1)-antitrypsin (AT) that evolved in the three phylogenetically representative Mus species, M domesticus, M caroli, and M saxicola. Specific questions of primary interest include: How have the hormonal regulatory elements within the AGP gene cluster been rearranged, and what new response elements have evolved in the Mus species in comparison to the single gene copy system of rat? What is the nature of the regulatory elements responsible for unusual renal expression of the AT gene in M caroli and M saxicola, and what controls the expression of the different genes in the liver during normal physiologic and stress states? Our fundamental goal is to define and characterize the cis- and trans-acting factors responsible for the evolutionarily-derived alterations in gene expression phenotypes. Our efforts will provide new information regarding the molecular machinery that controls the mammalian acute phase response and its evolution; such information will add significantly to our general understanding of gene transcription and its regulation in the mammalian liver.