This project is focused on two key findings: (1) Fish oil and omega-3 fatty acids prolong the duration of DNA replication in several proliferating cell lines and this effect is associated with a change in the location of a DNA replication origin; and (2) Levels of PDGF receptor mRNA are significantly increased in fibroblasts treated with fish oil. Dr. Istfan hypothesis is that fatty acids influence the spatial and temporal organization of replication origins by altering the structure of the nuclear membrane. The latter is thought to impact on the organization of the nuclear matrix which has been related to DNA replication origins through specific attachments (scaffold attachment regions, SARs). Alternatively, the degree of nuclear membrane fluidity, a function of fatty acid composition, affects the nuclear pore complex, thus altering the kinetics of nucleocytoplasmic trafficking. Dr. Istfan will test the extent of fatty acid incorporation into nuclear membranes in cell cultures and the cell-free Xenopus replicating system. Membrane fluidity and cell proliferation kinetics will be related to nuclear membrane fatty acids, nuclear membrane pore function, and nuclear matrix organization through studies of SARs and temperature-sensitive nuclear matrix proteins by confocal microscopy. Dr. Istfan also postulates that PDGF receptor regulation compensates for a reduced proliferation signal in fish oil-treated fibroblasts. Studies that examine the relationship between S phase lengthening in fish oil treated fibroblasts and regulation of the PDGF receptor will be initiated. The functional role(s) of this receptor and those of G1/S cyclins in mediating compensatory changes in G1 phase regulation will be examined.
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