GENETIC REGULATION OF THE HEPATIC ACUTE-PHASE RESPONSE

控制基因表达的分子机制在 进化，导致物种特异性改变的出现 基因调控模式。 对这些修改的分析提供了 新的见解的性质和作用机制的分子 决定基因活性的元件，并且是 进化的过程 为了解决这个问题，我们开发了 小鼠急性时相蛋白基因作为模型。 这些基因编码 由肝脏分泌的许多血浆蛋白协调地 在急性炎症过程中诱导;诱导是由 几种激素，包括白细胞介素-1， 白细胞介素-6和糖皮质激素。 重要的是，结构和 急性期基因的表达表现出广泛的变化， 老鼠的种类 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， 包括小鼠在内，这些基因的确切反应机制是 没有 在这次更新申请中，我们建议继续进行分子 急性时相蛋白基因种间变异的遗传分析 调控，重点是两个多基因系统的α（1）-酸 糖蛋白（AGP）和α（1）-抗胰蛋白酶（AT），它们在 三种具有代表性的家鼠属物种，M. tagiticus，M. caroli和岩生M. 主要关心的具体问题包括： AGP基因簇中的激素调节元件 被重新安排，以及在Mus中进化出了哪些新的反应元素 与大鼠的单基因拷贝系统相比， 是什么 负责异常肾功能的调节元件的性质 AT基因在M caroli和M saxicola中的表达，以及什么控制着 在正常情况下，不同基因在肝脏中的表达 生理和压力状态 我们的基本目标是定义和 描述顺式和反式作用因子， 基因表达表型的进化衍生的改变。 我们 这些努力将提供有关分子机制的新信息 控制着哺乳动物的急性期反应及其演变; 这些信息将大大增加我们对基因 转录及其在哺乳动物肝脏中的调节。

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.