REGULATION OF ACUTE PHASE REACTANT GENES DURING AGING

急性期反应是有机体对 感染、组织损伤、恶性生长或炎症。它 涉及一系列反应，包括激活 粒细胞和单核细胞与细胞因子的分泌和转运 从这些细胞到肝脏的介体，因此， 诱发多种血浆中血清水平的剧烈变化 蛋白质，急性期的反应物。急性期反应 似乎受益最大的是限制组织损伤和修复 动态平衡。 尽管人们对其背后的机制知之甚少 在急性发作期间调节基因表达的级联反应 时相反应，被认为是信号转导途径 是由细胞因子-细胞因子受体相互作用触发的。与 几种炎症相关细胞因子和细胞因子的分子克隆 体外系统的建立部分模仿了 急性期反应，现在可以识别警报 基因参与的信号、中间途径和参与者 急性时相反应的调控。重大进展 已经在鉴定急性时相诱导蛋白方面取得了进展 参与调控的因子和DNA顺式作用元件 呈阳性的急性期基因。然而，生理功能 这些因素和元素的特征是体外系统 仍需在体内进行研究。与积极的急性 阶段基因--负性急性期的基因调控方式 反应物仍不清楚。 关于基因表达调控的建议研究 急性相反应物在老化研究中尤为重要；它 对经常患有慢性病的老年人有医学上的影响 感染或炎症后恢复；它是一个模型 用于研究触发的基因表达调控的系统 在衰老过程中受到重要环境因素的影响。虽然只有一个 关于这个问题已经进行了少量的研究，它 似乎表达了几种急性期的反应物 在人类的衰老过程中是不同的。 在这个项目中，我们将比较大小和动力学 急性时相反应物在成熟期和成熟期体内的表达 老化的小鼠。蛋白质因子、DNA元件和介体 参与调节衰老过程中的急性期基因将 利用转基因小鼠系统进行研究。我们还将研究 人们对羽绒的分子机制知之甚少。 炎症过程中某些血浆蛋白基因的调控。

The acute phase reaction is a response of the organism to infection, tissue injury, malignant growth or inflammation. It involves a cascade of reactions including the activation of granulocytes and monocytes, the secretion and transport of cytokine mediators from these cells to the liver and, consequently, the induction of dramatic changes in serum levels of a number of plasma proteins, the acute phase reactants. The acute phase response appears to benefit the most by limiting tissue injury and restoring the homeostasis. Although little is known about the mechanisms underlying the cascade of reactions that modulate gene expression during the acute phase response, it is believed that signal transduction pathways are triggered by cytokine-cytokine receptor interactions. With the molecular cloning of several inflammation-associated cytokines and the establishment of in vitro systems that partially mimic the acute phase reaction, it is now possible to identify the alarm signals, the intermediate pathways and the players involved in gene regulation during the acute phase reaction. Significant progress has been made in identifying the acute phase-induced protein factors and the DNA cis-acting elements involved in the regulation of positive acute phase genes. However, the physiological function of these factors and elements characterized by in vitro systems remains to be studied in vivo. In contrast to the positive acute phase genes, the mode of gene regulation for negative acute phase reactants is still unclear. The proposed study about the regulation of gene expression for acute phase reactants is especially important in aging research; it has medical implications for the elderly who often suffer from slow recovery after infection or inflammation; and it serves as a model system for the study of the modulation of gene expression triggered by important environmental factors during aging. While only a small number of studies have been conducted on this subject, it appears that several acute phase reactants are expressed differently during senescence in humans. In this project, we will compare the magnitude and the kinetics of the expression of the acute phase reactants in vivo in mature and aging mice. The protein factors, DNA elements and mediators involved in the regulation of acute phase genes during aging will be studied using the transgenic mouse system. We will also study the poorly understood molecular mechanisms involved in the down- regulation of some plasma protein genes during inflammation.