Ex vivo models for follicle development and growth
We are currently using techniques for in vitro follicle development to more accurately study follicle formation across multiple mammalian model systems, including bovine, non-human primate, and human. This culture system will allow us to study human ovarian oocyte development in the context of the follicular microenvironment , including the precise mechanisms required for healthy follicle growth and the generation of fertilizable oocytes. This studies are important for our understanding of reproductive biology, and critical for the the development of stem cell-based strategies for ovarian replacement therapy or an artificial ovary.
A fully functional adult mammalian ovary consists of both germ cells and somatic support cells, most notably ovarian granulosa cells and their precursors. We are currently developing techniques to derive granulosa cells from human embryonic stem cells and induced pluripotent stem cells with the goal of generating a source of functional oocyte support cells that are also capable of maintaining steroid production in an organism as a potential alternative to conventional hormone replacement therapy.
We apply molecular strategies developed from a system-based proteomics approach to in vitro modeling studies, promoting the directed differentiation of stem cells to an ovarian granulosa cells by supplying the correct matrix environment, extracellular cues, and signaling molecules in a temporal sequence consistent with development. Using this strategy, stem cells provide an important model for human disease modeling, oocyte maturation, and steroid maintenance.
Mitochondria and Ovarian Cellular Energetics
As the 'powerhouse' of the cell, mitochondria are innately linked to the cellular function and aging phenotypes of every cell type, including ovarian cells. We are currently investigating the role of mitochondria in germ line integrity and ovarian function, using a mouse line containing a mitochondrial defect in polymerase gamma (POLG). These POLG mutator mice incur random mutations in their mitochondrial genomes and have a premature aging phenotype that results in a litany of age associated defects such as weight loss, and hearing loss, and notably reduced fertility.
In line with our interest in better understanding the role mitochondria play in aging, we have also developed novel analytic tools to evaluate individual mitochondrial subpopulations. Although mitochondria are typically referred to as the 'powerhouse' of the cell, mitochondria function in many cell type-specific capacities, and are known to exist in a heterogeneous population and act asynchronously within a single cell. Until recently, technical hurdles have prevented the study of mitochondrial dynamics in individual subpopulations of mitochondria. By understanding how the single nucleus of a given cell differentially targets specific mitochondria, we will gain a better understanding of the control of bioenegetics, mitochondrial biogenesis, and gain insight into cell-type specific mitochondrial functions. In aging cells, we have evidence that subpopulation dynamics shift and are working to determine the factors involved.