The common theme of the program project is analysis of events of the aging process that alter the synthesis of specific proteins important in responding to environmental adversities and physiological changes. Deviations in gene regulation are part of the underlying mechanisms of protein changes during aging. This application contains six projects and three cores and correlates DNA sequences with changes in gene regulation during aging. The work is being carried out by a group of molecular geneticists who have established track records in the genetic control of specific mammalian proteins described in each of their respective projects. The focus of the program is to study the effect of aging on the expression of 10 mammalian genes whose expressions typify the changes in regulation observed in aging. The corresponding protein products serve important roles in cell differentiation, cell proliferation, hormonal, heavy metal and inflammatory responses. The mammalian genes being studied are: several acute phase reaction genes, i.e., transferrin, haptoglobin and the alpha2-HS- glycoprotein; the gene for the growth factor receptor CSF1-R (c- fms); the cell adhesion protein, fibronectin, and its receptor; blood coagulation factor IX; the androgen receptor, a ligand- responsive nuclear transcription factor, as well as two reciprocally regulated androgen sensitive genes, i.e., alpha2u globulin and senescence marker protein 2. The same signals that govern expression of the 10 mammalian genes being analyzed here may also contribute to the pathogenesis of age-related problems such as atherosclerosis, arthritis, cardiovascular disease and impaired tissue repair. Progress has been made in analyzing age-modulated responses to signal transduction, structural alterations, inflammation, metal toxicity and hormonal changes. Recent technology is being utilized for the introduction of normal and chemically altered templates of genes to be studied into transfected cells capable of expressing each gene in vitro and into transgenic mice capable of expressing each gene in vivo.
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