Inorganic Signature of Activated Primordial Follicles (proposed)

One of the most compelling unanswered questions in human biology is how just one out of half a million  oocytes is selected each month to complete its development and ovulate. Each woman is born with a million  follicles, the fundamental units of the ovary, each containing a single germ cell (oocyte) surrounded by hormone-producing somatic cells (granulosa and theca). By puberty, that number is reduced by half and by menopause, all of the follicles will have been exhausted. Starting at puberty, the ovary must restrain the 500,000-follicle ovarian reserve for at least 4 decades of life, metering out follicles into the growing pool such that faithful ovulation of a single mature egg occurs each month. But what causes one follicle to be activated when a woman is 19 years old, while the follicle next to it remains inactive for 10, 20 or even 25 years? What are the signals of activation and restraint? How are the somatic and germ cells in inactive follicles protected  over long periods of time to maintain the regular hormonal fluctuations necessary for supporting women’s overall health and creating a viable egg that can be fertilized and give rise to healthy offspring? We propose to define the cellular mechanism that initiates growth of a small subset of follicles at a very specific point in time.  Our hypothesis is that if we combine powerful new technologies from chemistry, cell biology, physical and computational sciences, we can discover the integrated network of signaling cues required for follicle activation, what we call the ovarian calendar program.  We are now able to address this hypothesis because we have  developed  powerful new detection technologies and a new mouse line that tracks oocytes in different stages of development, and we have identified an important role for inorganic signals in the oocyte. We now have an unprecedented opportunity to identify the pathways regulating primordial follicle activation. But why should we study the mammalian egg when there are so many intractable problems in science, medicine, and public health? The oocyte is the origin of all of development, the progenitor of stem cells, and the cell upon which early regulators of adult disease are predicted to act, and holds the genetic information of all vertebrate animals. Discovering the mechanism by which oocytes are held in suspended animation and then activated at precise times during a woman’s life will not only answer a lingering question within reproductive biology that will impact women’s health, but will also reveal fundamental truths about cell activation that will impact broad areas of science and human health, including cancer, neurodegenerative disease, stem cell biology, and  regenerative medicine. Finally, we believe that solving the most intractable problems of our day requires teams who focus their unique expertise on solving that problem. The team members assembled for this project cross intellectual and technological boundaries, making possible the kind of transformative thinking necessary to create new paradigms for discovery. Using a team-based approach, the proposed work is expected to transform reproductive science and result in new technologies that can be applied to other cell systems.