REGULATION OF ACUTE PHASE REACTANT GENES DURING AGING

急性期反应是生物体对 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，细胞因子的分泌和转运 介质从这些细胞到肝脏，因此， 诱导一些血浆中的血清水平的显著变化， 蛋白质，急性期反应物。 急性期反应 通过限制组织损伤和恢复 体内平衡 尽管对这些疾病的潜在机制知之甚少， 在急性期调节基因表达的级联反应 相响应，据信信号转导途径 由细胞因子-细胞因子受体相互作用触发。 与 几种炎症相关细胞因子的分子克隆， 体外系统的建立，部分模拟 急性期反应，现在可以识别警报 信号，中间途径和参与基因 在急性期反应的调节。 重大进展 急性期诱导蛋白的鉴定 参与调控的因子和DNA顺式作用元件 急性期阳性基因 然而，生理功能 这些因素和要素的特点是在体外系统 还有待于在体内进行研究。 与积极的急性 时相基因，负急性期的基因调控模式 反应物尚不清楚。 本研究拟对基因表达调控进行研究， 急性期反应物在衰老研究中尤其重要， 对那些经常患有慢性疾病的老年人来说， 感染或炎症后的恢复;它作为一个模型， 用于研究基因表达调控的系统 在老化过程中受到重要环境因素的影响。 虽然仅 关于这个问题进行了少量的研究， 似乎有几种急性期反应物表达 在人类衰老过程中的不同。 在这个项目中，我们将比较的幅度和动力学 急性期反应物在体内成熟和成熟细胞中的表达， 衰老的老鼠 蛋白质因子、DNA元件和介质 参与衰老过程中急性期基因调控的基因 使用转基因小鼠系统进行研究。 我们还将研究 人们对这种疾病的分子机制知之甚少， 炎症过程中某些血浆蛋白基因的调节。

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.