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. During a woman's thirties, the incidence of meiotic segregation errors increases exponentially such that the risk of an aneuploid pregnancy for a woman in her early forties exceeds 30%. Such errors are the leading cause of birth defects and miscarriages in humans. Although the link between maternal age and meiotic nondisjunction (NDJ) is well- established, the molecular mechanisms underlying this phenomenon remain poorly understood. One prerequisite for accurate chromosome segregation is sister chromatid cohesion, the protein-mediated linkages that hold sister chromatids together. Meiotic cohesion must remain intact 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 loss of cohesion as oocytes age contributes to the maternal age effect. Using Drosophila as a model system, we have recently discovered that accurate chromosome segregation requires a ?rejuvenation? program that establishes new cohesive linkages during prophase I.
Aim 1 will use a number of approaches to define the molecular events that underlie cohesion rejuvenation in Drosophila oocytes. Consistent with the proposal that accumulation of oxidative damage in aging oocytes may contribute to the maternal age effect, our recent work provides the first in vivo demonstration that oxidative stress induces meiotic segregation errors.
Aim 2 will further delineate the mechanism(s) by which oxidative stress causes NDJ by identifying oocyte proteins that incur oxidative damage. In addition, using our standardized age-dependent NDJ assay, we will determine whether loss of cohesion in Drosophila oocytes that undergo aging can be suppressed by increased levels of Superoxide Dismutase in the oocyte or by nutritional strategies known to reduce oxidative damage and/or extend lifespan. Sirtuins regulate several aspects of cellular homeostasis and reduced Sirtuin activity is associated with aging.
Aim 3 will test the hypothesis that reduced Sirtuin activity during meiotic prophase causes premature loss of cohesion that leads to NDJ and determine whether Sirtuin knockdown elicits an increase in oxidative damage and/or modulation of Superoxide Dismutase activity in oocytes. We also will determine whether dietary supplements known to increase Sirtuin activity can suppress age-dependent NDJ. Our experiments will provide a better understanding of the normal pathway(s) that keep meiotic cohesion intact, the mechanisms that lead to loss of cohesion with age and insight regarding the ability of nutritional strategies to suppress age-dependent NDJ. As such, the proposed work addresses an unresolved reproductive health issue that has a major impact on the pregnancy outcomes of older 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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