The long-term goals of my laboratory are to elucidate the mechanisms that regulate sister chromatid cohesion and chromosome segregation during meiosis and to understand why meiotic chromosome segregation errors in human oocytes increase as women age. The incidence of meiotic segregation errors increases dramatically as women age. Such errors are the leading cause of birth defects and miscarriages in humans but the molecular mechanisms underlying this phenomenon (termed the maternal age effect) are not well understood. One prerequisite for accurate chromosome segregation is sister chromatid cohesion, the protein-mediated linkages that hold sister chromatids together. In human oocytes, meiotic cohesion must be maintained for decades, from the time it is established in the fetal ovary until ovulation triggers resumption of meiosis and anaphase I. Several lines of investigation support the model that age-induced loss of cohesion contributes to the maternal age effect. We have discovered a ?cohesion rejuvenation? program in Drosophila oocytes that establishes new cohesive linkages during prophase I and our recent genetic screen has identified several candidate rejuvenation players.
Aim 1 will use a number of approaches to further delineate the mechanism(s) underlying rejuvenation. For over two decades, accumulation of oxidative damage in aging oocytes has been proposed to contribute to the maternal age effect. My lab recently provided the first causative link between oxidative stress incurred during meiotic prophase and premature loss of meiotic cohesion. Moreover, we have demonstrated that a moderate increase in the enzymes that scavenge superoxide radicals can significantly decrease age-induced segregation errors in Drosophila oocytes. Our recent proteomics efforts have identified proteins that suffer oxidative damage when oxidative stress is induced during meiotic prophase.
Aim 2 will test the hypotheses that one or more of these identified candidates are required to maintain meiotic cohesion and that their ability to do so is compromised by oxidative damage incurred during oocyte aging. Sirtuins regulate several aspects of cellular homeostasis and reduced sirtuin activity is associated with aging. In addition, mounting evidence suggests that sirtuins protect cells, at least in part, by modulating autophagy. Our recent findings support the hypothesis that at least two Drosophila sirtuins are required to maintain cohesion during meiotic prophase.
Aim 3 will investigate the intersection between sirtuin activity and autophagy in the maintenance of meiotic cohesion and how aging impacts these processes. Through genetic and proteomic screens, we have uncovered several unexpected connections between cohesion rejuvenation, oxidative stress and autophagy in the oocyte that uniquely position us to make fundamental discoveries regarding the mechanisms that maintain meiotic cohesion and how these are impacted by aging. Our work addresses a major reproductive health issue that impacts the pregnancy outcomes of many women.
Meiosis is a specialized type of cell division that gives rise to eggs and sperm. In humans, errors during meiosis are the leading cause of miscarriages and birth defects such as Down Syndrome. The experiments in this proposal are designed to elucidate the mechanisms that operate during normal meiosis, to understand the defects that give rise to errors during human meiosis, and to test nutritional strategies that may reduce these errors.
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