Humans over the age of 60 generally exhibit hemostatic imbalances; for example, hypercoagulation and intravascular coagulation are frequently observed in the elderly. It has been observed that severe coagulation factors increase with age, resulting in a predisposition to thrombosis. Studying the biosynthesis of coagulation factors during aging will add to our knowledge of the mechanisms involved in developing a prethrombotic state in the elderly. In this application, we have focused on factor IX biosynthesis during aging. Human factor IX is a glycoprotein which participates in the intrinsic pathway of blood coagulation. It is synthesized as a zymogen in the liver; cleavage by XIa causes factor IX to become an active enzyme having serine protease activity. The deficiency of human factor IX leads to an X-lined bleeding disease termed hemophilia B. One variant, hemophilia B-Leyden, has the following characteristics: from birth to puberty the hemophilia B-Leyden male has virtually no factor IX in his blood; as he reaches puberty, his factor IX level reaches 20-30% of normal and continues to increase to about 60% in elderly patients. In this variant, possibly the activation of a repressed gene at puberty results in increased synthesis of factor IX. Several distinct mutations causing the hemophilia B-Leyden phenotype have been characterized. How such mutations may be involved in causing synthesis of larger amounts of factor IX during aging has not been determined. In this regard, it is of interest that factor IX levels increase with age in all humans, but at a much faster rate in post-puberty male hemophilia B-Leyden patients. The current hypothesis is that steroids activate the gene and other factors continue to enhance the synthesis of factor IX during aging. This effect is more pronounced in the hemophilia B-Leyden mutation compared to the normal gene and thus the factor IX gene offers an excellent model system to study transcriptional regulation during aging, with a long-range goal of understanding the compensatory mechanisms for the predisposition to thrombosis during aging. In this application we propose to determine the mechanisms responsible for factor IX gene transcription during aging. This will be accomplished by identifying cis-regulatory sequences for factor IX gene transcription and studying induction of the gene in transgenic mice during aging.
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