Amino acids are important precursors of fetal protein synthesis. Placental transfer of amino acids in sufficient quantities is, therefore, necessary if adequate fetal growth is to occur. This is of particular importance during the third trimester, when the fetus requires the transfer of 40-60 mmols of amino acids from the maternal to the fetal circulations each day. The placenta also functions to clear potentially toxic amino acids, prominently glutamate, from the fetal circulation. This amino acid is then metabolized, with subsequent production of NADPH, important as an energy source for placental androgen synthesis, as well as other energetic intermediates. The long- term goal of our research is to delineate the regulation of placental amino acid transport in both normal and pathologic pregnancies. Placental amino acid transport is affected in two models of intrauterine growth retardation, and is regulated over gestation. The purpose of this proposal is to begin to define the mechanisms by which these changes occur, with the major focus upon transport proteins known to participate in the placental transfer of glutamate, specifically EAAC1, GLT1, and GLAST1, responsible for Na+-dependent anionic amino acid transport via System X-AG. Proposed experiments will 1) delineate cell populations within the placenta which participate in the transport and metabolism of these amino acids, 2) determine the contribution of mRNA transcription rates to the ontogenic changes previously defined and 3) determine, on the ultrastructural level, the distribution of these transport proteins. Subsequent experiments will characterize anionic amino acid transport in cell lines derived from rat placenta, define the presence and contribution to transport of the anionic amino acid transport proteins described above, and explore the influence of glutamate availability and of the insulin-like growth factors and insulin upon the transcription, translation, and expression of these amino acid transport proteins. Finally, we will explore the physiologic relevance of glutamate transport and metabolism in placental cells. Specifically, the impact of glutamate metabolism and transport upon glucose utilization and placental androgen synthesis will be determined. These studies will significantly advance our understanding of the regulation of and interrelationships between nutrient transfer and metabolism in the developing fetoplacental unit.
| Novak, Don; Quiggle, Forest; Haafiz, Allah (2006) Impact of forskolin and amino acid depletion upon System A activity and SNAT expression in BeWo cells. Biochimie 88:39-44 |
| Novak, D; Lehman, M; Bernstein, H et al. (2006) SNAT expression in rat placenta. Placenta 27:510-6 |
| Novak, D; Quiggle, F; Matthews, J (2004) Androgen secretion by Rcho-1 cells is independent of extracellular glutamate concentration. Placenta 25:548-52 |
| Cramer, Stuart; Beveridge, Mark; Kilberg, Michael et al. (2002) Physiological importance of system A-mediated amino acid transport to rat fetal development. Am J Physiol Cell Physiol 282:C153-60 |
| Novak, Donald (2002) Nutrition in early life. How important is it? Clin Perinatol 29:203-23 |
| Novak, D A; Kilberg, M S; Beveridge, M J (1994) Ontogeny and plasma-membrane domain localization of amino acid transport system L in rat liver. Biochem J 301 ( Pt 3):671-4 |
