This Section carries out research on the biological role and mechanisms of action of insulin-like growth factors -I and -II (IGFs-I and -II). These particular growth factors have major roles in development as proven by the fact that targeted deletion of IGF-I and IGF-II gene expression results in severe dwarfism and, in the case of IGF-I, 90% mortality~ although how IGF deletion causes these defects is not yet understood. Molecular, immunological and radioligand probes are used to analyze the cellular sites of synthesis and action of these growth factors, their putative regulators and potential targets during embryonic development as well as in different physiological and pathophysiological situations in which IGFs have key roles. This Section has made progress over the past year in dissecting the signal transduction pathways and biological functions of IGFs in the brain. A specific protease termed IDE has been implicated in selective termination of IGF induced signalling and two distinct cGMP-inhibited phosphodiesterase isoforms (PDE3A and PDE3B) have been implicated in IGF signal transmission in the developing and mature brain, respectively. Spatiotemporal patterns of IGF system expression have been docummented in the developing chick brain, establishing the fundamental conservation of expression patterns and probable roles in avian and mammalian species. Additional studies have implicated specific IGF system responses in recovery from acute and chronic ischemia and a variety of demyelinating diatheses. The group has defined the mechanism by which IGF-I promotes ovarian follicluar selection, showing that this intrinsically produced peptide stimulates granulosa cell division and FSH receptor expression, thus regulating gonadotropin responsiveness and ultimately estrogen production and ovulation. A non-human primate model is being developed to study the effects of different menopausal hormone replacement therapy regimens on local growth factor production and tissue hyperplasia in female reproductive organs. A major new finding is that the addition of progesterone to estrogen treatment produces a drastic upregulation of IGF-I in the primate myometrium which is strongly correlated with myometrial proliferation. These data are predicted to have major impact with regard to the design of hormone replacement therapy regimen for women at risk for myometrial tumors and for treatment of leiomyomas.
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