OVARIAN PRIMORDIAL FOLLICLE DEVELOPMENT
The proposed research is directed toward developing a better
understanding of the mechanisms that control primordial follicle
development. This process is essential for the establishment and
maintenance of female reproduction. Primordial follicle development
involves the initial event of primordial follicle assembly and the
subsequent event of primordial to primary follicle transition. The
process involved in primordial follicle assembly is distinct from
that of primordial to primary follicle transition and both will be
investigated in the proposed research. The manner by which locally
produced ovarian substances and hormones regulate these processes
are of particular interest. Emphasis is placed on the elucidation
of cell-cell interactions between precursor theca cells, granulosa
cells and the oocyte. Previous research and preliminary studies
have demonstrated that the control of primordial follicle
development and subsequent folliculogenesis appears to be mediated
by the local production and action of specific paracrine factors
involving theca cells, granulosa cells, and the oocyte. Preliminary
studies have shown that steroid hormones (i.e. estrogen and
progesterone) play a critical role in the onset of primordial
follicle assembly. Preliminary studies also demonstrate that
primordial to primary follicle transition requires integrated
interactions between the oocyte, granulosa cells and precursor
theca cells involving kit ligand (KL), basic fibroblast growth
factor (bFGF), leukemia inhibitory factor (LIF), keratinocyte
growth factor (KGF) and bone morphogenic protein-4 (BMP4).
"THE GENERAL HYPOTHESIS TESTED IS THAT HORMONES
INFLUENCE THE PARACRINE GROWTH FACTOR MEDIATED INTERACTIONS BETWEEN
THE OVARIAN SOMATIC CELLS AND THE OOCYTE TO CONTROL PRIMORDIAL
FOLLICLE ASSEMBLY AND DEVELOPMENT". More defined
sub-hypotheses are presented for each specific aim below.
Interactions between hormones and paracrine growth factors provide
an efficient mechanism to control primordial follicle development.
It is anticipated that abnormalities in these cellular interactions
will influence female fertility, menopause onset and promote
pathophysiologies such as premature ovarian failure. The
experimental approach consists of the following specific aims:
1) Elucidate the hormonal and paracrine growth factor control of
primordial follicle assembly. 2) Elucidate the hormonal and growth
factor control of the primordial to primary follicle transition. 3)
Elucidate the physiological importance of specific factors that
mediate primordial follicle development. Completion of these
specific aims will extend previous observations and provide insight
into the role of growth factor mediated cell-cell interactions in
regulating primordial follicle development. The critical
developmental periods to be examined include the induction of
primordial follicle assembly and the primordial to primary follicle
transition. It is anticipated that the specific cell-cell
interactions will change between these developmental periods. The
differential effects of hormones on growth factors and relevant
receptors have a critical role in later stages of follicle
development, but remain to be determined in primordial follicle
development. Observations are anticipated to provide insight into
the molecular and cellular control of primordial follicle
development. The information obtained will be used to understand
the onset of puberty and menopause, as well as provide insight into
the potential future design of diagnostic procedures and
therapeutic treatments for abnormal ovarian conditions such as
premature ovarian failure (POF) and forms of female infertility. An
example of a future experiment proposed is to determine if
mutation(s) exist in any of the repertoire of growth factors and/or
receptors established in the current study as potential causal
factors for disease states such as premature ovarian failure.