Decreased peak bone density, increased embryonic aneuploidy, and decreased fertility are each clinical examples of the onset of a perimenopausal transition which begins in the mid-thirties. This project is directed at understanding the biological basis of this transition by investigating granulosa cells which are fundamental components of the aging follicle. The overall goal of this project is to investigate age-dependent changes in the human granulosa cell. The working hypothesis is that reproductive aging results in an ovarian follicle containing somatic cells (granulosa cells) and germ cells (oocytes) which are of compromised quality (diminished ovarian reserve) as compared to their respective components in younger women. As healthy granulosa are essential for oocyte viability this proposal focuses upon cellular and genetic aspects of granulosa cells within the follicle. The study will explore how age-dependent alterations in the granulosa cell cycle can lead to default pathways resulting in increased granulosa cell apoptosis. An investigation into whether the differential expression of the Bcl-2 gene family and/or an increase in mitochondrial mutations are associated with an increased rate of granulosa cell apoptosis found in women with diminished ovarian reserve will be made. Finally, the mitochondrial mechanisms by which granulosa cell apoptosis occurs as a function of diminished ovarian reserve will be explored.
The specific aims are: 1) to evaluate the age-related differences in cell cycle kinetics of granulosa cells and to determine if these changes are associated with different rates of apoptosis in granulosa cells, 2) to examine age-related differences in mitochondrial DNA mutations, nuclear-coded mitochondrial genes and Bcl-2 gene family expression as a function of diminished ovarian reserve, 3) to investigate the mitochondrial mechanisms by which granulosa apoptosis occurs as a function of diminished ovarian reserve.
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