REGULATION OF ACUTE PHASE REACTANT GENES DURING AGING

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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.