Genetic and molecular mechanisms of age regulation (homeostasis) of blood coagulation.

Blood coagulation plays a critical role not only in hemostasis but also in many physiological and pathological conditions. Epidemiological studies have shown that blood coagulation capacity in humans increases with age. Towards understanding the underlying mechanisms, the age regulation of factor IX, a key blood coagulation factor, was extensively studied. A series of human factor IX minigenes, consisting of various components of the human factor IX gene, were constructed and subjected to systematic analyses with HepG2 cells in culture and over the entire life span of transgenic mice. These studies identified critical gene structures that are essential for the unique age-dependent expression patterns of the human factor IX gene--one acting by stabilizing gene transcription and another increasing the amount of mRNA present, presumably by augmenting mRNA stability. These studies have set the stage for analyzing the overall age-based regulatory mechanisms of blood coagulation.