The program tests the proposition that normal growth and organogenesis in the postimplantation embryo are linked to the integrity of ongoing metabolism. The studies focus on early organogenesis insofar as vulnerability to all teratogens is greatest and the embryo's metabolic repertoire is most limited at that time. Two aspects of metabolism are examined: energy generation and signal transduction. Energy balance may be delicately poised because aerobic glycolysis is the principal source of energy for much of this period. Accordingly, the studies will (a) assess selected points in glycolysis which may be critical for glycolytic regulation (e.g. 6-phospho-fructo-1-kinase; fructose 2,6-bisphosphate); (b) evaluate the effects on glycolysis as well as gene expression of certain growth factors (e.g. insulin; IGF-I; IGF-II; PDGF; EGF; etc.) which can influence glycolysis and may regulate the subsequent expression of other mRNAs necessary for orderly morphogenesis; and (c) correlate the developmental chronology with the concurrent levels of gene transcript for other factors such as glucose transporter and insulin receptor which may be linked to glycolytic activation and phenotypic transformations. Signal transduction may be precariously balanced because the embryo's content of myo-inositol (i.e. the precursor for the phosphoinositides which serve as """"""""storage forms for messenger molecules"""""""") is relatively low and subject to further reductions by transport competition with glucose. Accordingly, the studies will a) assess myo-inositol transport and the attendant turnovers of phosphoinositides under steady state conditions and in response to growth factors which may require the cleavage of phosphoinositides for transduction; and b) evaluate the relationship to """"""""high glucose"""""""" embryopathy by examining effects of """"""""high glucose"""""""" on myo- inositol and phosphoinositide turnover, and gene expression of growth factors which may be """"""""triggered"""""""" by the hydrolysis of phosphoinositide at certain stages of development. Most studies will be conducted with cultured intact rat embryo since much of the period of postulated metabolic vulnerability can be replicated with this preparation in vitro. Infusion techniques with an agent (mannose) which perturbs glycolysis during early organogenesis in the conceptus without disturbing the mother will be employed for more prolonged analysis of """"""""metabolic-morphologic interactions"""""""" in vivo. The studies should provide new insights concerning the pathogenesis of birth defects in normal pregnancies and pregnancies complicated by diabetes.
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