Dr. Johnson's Lab
Inferility is not the only problem faced by women that experience POF. Loss of ovary function results in significant health and well-being compromises for the remainder of a woman’s life. Bone density, cardiovascular health, muscle mass, body fat composition, and other self-reported well-being measures worsen upon ovarian failure. Unfortunately, existing treatment for these issues, hormonal replacement, has mixed success alleviating symptoms, and can associate with increased health risks. These significant health problems offer compelling motivation to uncover general causes of POF so that we may develop prevention strategies.
In an ongoing project assessing the involution of dying ovarian follicles, we uncovered a link between nutritional stimuli and both oocyte quality and oocyte survival. We published evidence that inhibition of the TOR pathway results in the activation of a stereotyped process of oocyte destruction by adjacent somatic (in mammals, granulosa) cells conserved from fruit flies to humans. A striking novel finding made by our group is the identification of empty mammalian follicles that lack oocytes that result from oocyte destruction. Empty follicles are thus a previously-underappreciated intermediate stage in the atresia (death) of immature follicles.
We have funding to study Fragile X associated premature ovarian insufficiency (FXPOI). Preliminary data in that project reveals the developmental timing and modality of oocyte loss for the first time in a mouse model of FXPOI. Women who carry Fragile X gene FMR1"premutation" DNA repeats are at risk of developing Fragile X–associated primary ovarian insufficiency (FXPOI) and early menopause. Unfortunately, mechanisms instigated by the premutation that result in ovarian dysfunction are unknown. As part of a multi-center collaboration, we use human, mouse, and Drosophila CGG repeat models that will allow us to identify and dissect these mechanisms. We have designed these studies so that we can identify clinically-relevant/ translational targets of the FMR1 repeat in order to protect ovarian function. By combining epidemiological, molecular genetic, and physiological approaches, we will maximize the likelihood of uncovering the factors responsible for oocyte loss in FXPOI. If we can determine how and why oocyte loss occurs in the case of the Fragile X premutation, we may be able to extend the duration of ovarian function for afflicted human patients and thus improve critical measures of health and well-being, and if desired, fertility. These studies will inform our overall goal, protecting ovarian function in all women.