Research Interests

Our overarching goals are to discover key aspects of ovarian development that underpin our understanding of infertility and endocrine diseases involving the ovary, and to develop prevention and treatment strategies for these. My group, in collaboration with many others, focuses on the roles of extracellular matrix. Matrix is diverse and complex and regulates many cellular and tissue functions. It has been largely overlooked in comparison with the numerous studies of hormones and growth factors in the ovary and hence holds potential for many new discoveries.

Research Projects

1. Mechanism of Fetal Predisposition to Polycystic Ovary Syndrome: While the precise aetiology of PCOS is yet to be determined, several familial studies from others have demonstrated an association between PCOS and the dinucleotide repeat microsatellite marker D19S884. D19S884 is located within intron 55 of the extracellular matrix gene fibrillin 3 gene. Studies of fibrillins 1 and 2 have shown that they function both as structural components of elastin fibres or mircrofibrils and as regulators of TGFβ family members. Regulation of TGFβ activity by fibrillins is a result of their ability to bind to latent TGFβ binding proteins causing sequestration of latent TGFβs into the extracellular matrix where they are stored and/or activated. TGFβs stimulate collagen production by fibroblasts and are up regulated in fibrosis. The PCOS ovary has increased trunica albunigea and stroma and collagen deposition in these layers. We published two large studies by Ray Rodgers (Molec Cell Endo 307, 133; Molec Human Reprod 15, 829) where we failed to find any role of fibrillin 3 in adult ovaries.  Then in a landmark study we showed that fibrillin 3 was found to be expressed in the developing stroma of human and bovine fetal ovaries (FASEB J 25, 2256-2265).  This study mechanistically combined three important observations about PCOS: (a) The fetal origins of PCOS, (b) The genetic studies suggesting that fibrillin 3 could be a candidate gene in PCOS and (c) The PCOS ovarian phenotype with altered stromal compartments (tunica albuginea, cortical stroma, theca interna); the hallmarks of enhanced TGFβ activity.  Note that this is also the first time TGFβ had been implicate in the aetiology of PCOS.

2. Formation of the Ovary:  The continued study of PCOS necessitated studying the fetal ovary.  It soon became clear the current hypotheses on how the ovary develops, and as described in anatomy text books are not correct.  We identified how the ovary and follicles develop during fetal development (PLOS ONE 8(2):e55578).  Importantly we identified a novel cell type, GREL (Gonadal-Ridge Epithelial Like) cells, that are the precursor cells of both the surface of the ovary and the follicular granulosa cells.  We identified the surface epithelium at the base of the ovary differs in its developmental origins that the rest of the ovary, perhaps explaining the difference in their stemness and oncogenic potential observed between these two regions of the ovary surface (Nature 2013;495:241-5).

3. Regulation of Thecal Androgen Production:  Androgen production by the theca cells is the cause of hyperandrogenia in PCOS women.  A hormone INSL3 whose role was not understood is also expressed in the thecal cells.  Early studies by us and collaborators (Biol. Reprod. 66, 934-943) found it be dynamically regulated during follicular growth and atresia.  In collaboration with Prof Phil Knight of Reading University is has now been shown to be regulated by BMPs and to stimulate androgen production by the thecal cells (Proc Natl Acad Sci USA  110, doi =10.1073/pnas.1222216110).

4. Oocyte Quality: Whilst studying the follicular basal laminas we discovered in bovine (J. Reprod. Fertil. 118, 221-228) and in humans (Human Reprod. 24, 936-944) that follicles have one of either of two phenotypes of follicular basal lamina.  We believe these are formed by differential rates of follicle antrum expansion (Biol Reprod 82, 1021–1029). These forms are related to the quality of oocytes within them based upon their ability to mature in vitro (Human Reprod. 24, 936-944).  Both follicles are healthy. Using a combination of microarrays, proteomics and metabolomics we are identifying molecules differentially present in these follicles that could be used as biomarkers for each follicle type. Significant savings and improvements in ART should be possible if we could choose the better embryos for uterine transfer in IVF programs, thus increasing success rates.

5. Focimatrix and Maturation of Follicles: We have identified many components of matrix and the changes they undergo in developing follicles, atretic follicles, ovulating follicles and resultant corpora lutea. We also identified a novel type of basal lamina matrix, called focimatrix, which is developmentally regulated in the later phases of follicular growth (Matrix Biol. 23, 207-217.). The novel aspect of this matrix is its conformation. Basal laminas are normally a sheet of matrix ‘wrapped' around a cell or a group of cells (epithelia or endothelia). Therefore basal laminas make compartments within tissues. Focimatrix, however, does not form a continuous layer and thus it cannot perform known basal lamina functions. Our recent data suggest that focimatrix is the key to a follicle developing dominance over other follicles in the follicular phase of the cycle (Mol Cell Endo 321, 207-214; Reproduction 137, 825-834). Studies into its regulation and function maybe useful in improving fertility both in PCOS women and in IVF programs.

6. Formation of Follicular Fluid: Growth of the follicle encompasses enlargement of the oocyte, replication of follicular cells and formation and expansion of a central follicular antrum or cavity. Many in vitro studies of follicular growth have focused on the replication of granulosa cells, whilst in vivo studies using ultrasonography have focused on the expansion of the follicular antrum and its fluid. Replication of follicular cells and expansion of the follicular antrum are both important, and both are probably stimulated by some of the same hormones and growth factors. They are, however, very distinct processes. Our central hypothesis on follicular fluid formation, which is based upon our data, suggests that production by granulosa cells of hyaluronan and the chondroitin sulfate proteoglycan versican generate an osmotic gradient to draw in fluid from the thecal layer (Reproduction 132, 119-131; Biol Reprod 82, 1021–1029).