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Spatial and temporal modulation of initiation of ovarian follicle growth

Reference	BB/C514274/1
Principal Investigator / Supervisor	Professor Kate Hardy
Co-Investigators / Co-Supervisors	Professor Stephen Franks, Professor Jaroslav Stark
Institution	Imperial College London
Department	Surgery and Cancer
Funding type	Research
Value (£)	401,064
Status	Completed
Type	Research Grant
Start date	01/09/2005
End date	30/06/2009
Duration	46 months

Abstract

Little is known about the regulation of initiation of follicle growth in the mammalian ovary, which is thought to be a crucial factor in maintaining the appropriate reproductive lifespan for a given species. Knockout, expression or culture studies have implicated several members of the TGF-beta superfamily in this regulation. Over the past three years, we have collected detailed data from the neonatal mouse ovary on a) the growth of oocytes, and b) the spatial localisation of resting and growing oocytes within the ovary. Naive examination of the data suggest i) that follicles grow in waves and larger follicles produce an inhibitory factor that feeds back into the pool of resting follicles and prevents them initiating growth and ii) that primordial follicles themselves may produce an inhibitory factor of fixed range which is involved in maintaining the primordial pool. However, it is becoming increasingly clear these data require mathematical approaches of greater sophistication than standard statistics for their analysis, and hence we have decided to propose a dynamic collaboration between a laboratory-based group with expertise in ovarian physiology and a mathematician with an interest in modelling biological systems. This collaboration, which will employ one mathematical and one biological post-doc, will develop new mathematical models to analyse the temporal and spatial features of the existing data sets, and propose new hypotheses. Meanwhile, the biological post-doc will produce new experimental data, which will include the identification of new key regulatory candidates, by determining and quantifying expression of ligands, receptor and antagonists of the TGF-beta family in mouse neonatal ovary. Key candidates for negative feedback loops (AMH and activin are current such candidates) will be quantified in precisely mapped and measured follicles to provide data for constructing models of the spatio-temporal dynamics of follicle development. A further dimension will literally be added to this model, by collecting data on the 3-dimensional localisation of resting and growing follicles using confocal microscopy. Finally, the key candidate regulatory factors identified in the previous experimental and mathematical studies will be tested in culture by injecting peptide-saturated beads into neonatal ovaries in culture, and examining the effects on follicle growth. Meanwhile, simple feedback loops which have been developed on the basis of expression and culture studies by other groups will be developed further and extended by incorporating the spatio-temporal models of follicle dynamics developed in this programme. The combination of these approaches will result in the first integrated quantitative understanding of the network of mechanisms that determines the initiation of follicle growth.

Summary

unavailable

Committee	Closed Committee - Engineering & Biological Systems (EBS)
Research Topics	Ageing, Systems Biology, Technology and Methods Development
Research Priority	X – Research Priority information not available
Research Initiative	X - not in an Initiative
Funding Scheme	X – not Funded via a specific Funding Scheme

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