We plan to make use of human and animal cell cultures in an interdisciplinary study focused on the cellular and molecular biology of aging. The long-range goals are to understand the molecular processes that lead to age-related deteriorative changes in humans. A major component of this study will be to further understand the processes that lead to cellular senescence in human diploid fibroblast cells. These studies will include cloning and characterization of sequences that code for inhibitors of DNA synthesis that are present in senescent human diploid fibroblast cells and preliminary experiments to study the mechanism of action of the senescence cell inhibitor. Other studies will focus on the mechanisms of immortalization of human diploid cells to understand what normal cell functions have been modified in immortal cells and therefore are important in controlling cell proliferation in senescent cells. Another important aspect is to understand which coordinately expressed in proliferating and nonproliferating states. Studies of the effect of cell proliferation and cell quiescence per se on gene expression in cells that do not senescent but do retain tissue-specific function will attempt to elucidate this question. The role of mutagenesis in aging will also be studied. This will be done by comparing the rates of mutation in cells from patients exhibiting premature aging and DNA repair defects with those from normal donors. This project complements the others in the program project in that it will use cells in culture to ask direct questions about the mechanisms of aging in vivo.
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