Russell V. Anthony Hill Professor Department of Biomedical Sciences CSU Ph.D., University of Wyoming, 1983 ARBL-Foothills Campus Colorado State University Phone: 970-491-2586 Russ.Anthony@Colostate.edu

The placenta is a multifaceted organ that plays critical roles in maintaining and protecting the developing fetus. These roles include nutrient transfer from the mother to the fetus and waste secretion from the fetus to the mother, acting as a barrier for the fetus against pathogens and the maternal immune system, and as an active endocrine organ. My research is directed at characterizing the communication between the developing fetus and the utero-placental unit that is required for normal fetal growth and development to occur.

Transcriptional Regulation and Function of Placental Hormones: As an active endocrine organ, the placenta is capable of secreting a plethora of hormones, growth factors and cytokines. DNase footprinting, electrophoretic mobility shift assays, super-shift assays, two-base pair transversion mutations, overexpression studies and RNA interference studies are being used to examine transcriptional regulation of placental proteins. Proline-rich 15 (PRR15) is a newly described gene expressed during the window of conceptus apposition and expansion, as well as later in gestation within the human and sheep placenta, kidney and lung in a variety of species. PRR15 is a nuclear protein which we believe may act as a coactivator/corepressor of transcription during this critical window of conceptus development. We generated recombinant PF for antibody production, along with short hairpin RNA (shRNA) cassettes for use in RNA interference to examine the function of PRR15. In vivo lentivirus-mediated stable transfection of sheep blastocysts (day 8) effectively "knockeddown" PRR15 expression during conceptus development, resulting in cessation of development and conceptus demise by day 15. This approach is also being applied in vivo in mice and in vitro with human trophoblast cells to determine the role of PRR15 in establishing pregnancy, as well as to other genes expressed by the developing placenta.

Placental Development and Function: Fetal growth restriction (FGR) is a significant cause of infant mortality and morbidity, and near-term these fetuses are hypoxic, hypoglycemic and hypertensive, as a result of the altered placental development and functional placental insufficiency. We are using several approaches to generate FGR pregnancies in sheep, in which the fetus may be instrumented to directly monitor the fetus as a means of determining the factors involved in placental and fetal growth restriction. We have determined that placental vascular structure is altered in these FGR pregnancies, resulting from both acute and chronic changes in the experession of the growth factors and receptors responsible for driving placental vasculogenesis and angiogenesis. Due to the role that fetal hypoxia may play in altered fetal development within FGR pregnancies, and the impact that this may have on postnatal well being, we are examining the impact of development stage-specific prenatal hypoxia in rats. Our studies indicate that a window of prenatal hypoxia (day 12-15) impacts postnatal glucose homeostasis and insulin sensitivity, as well as right ventricular structure and function in the adult offspring,

Selected Publications

Regnault, T.R.H., R.J. Orbus, B. de Vrijer, M. Davidsen, S.W. Limesand, H.L. Galan, R.B. Wilkening and R.V. Anthony. 2002. Placental expression of VEGF, PlGF and their receptors in a model of placental insufficiency-intrauterine growth restriction (PI-IUGR). Placenta 23:132-144.

Regnault, T.R.H., B. deVrijer, H.L. Galan, M.L. Davidsen, K.A. Trembler, F.C. Battaglia, R.B. Wilkening and R.V. Anthony. 2003. The relationship between transplacental O2 diffusion and placental expression of PlGF, VEGF and their receptors in a placental insufficiency model of fetal growth restriction. J. Physiology 550: 641-656.

Limesand, S.W., K.M. Jeckel and R.V. Anthony. 2004. Pura, a single-stranded DNA binding protein, augments placental lacogen gene transcription. Mol. Endocrinol. 18:447-457.

Wallace, J.M., T.R.H. Regnault, S.W. Limesand, W.W. Hay, Jr. and R.V. Anthony. 2005. Investigating the causes of low birth weight in contrasting ovine paradigms. J. Physiology 565:19-26.

de Vrijer, B., M.L. Davidsen, R.B. Wilkening, R.V. Anthony and T.R.H. Regnault. 2006. Altered placental and fetal expression of IGFs and IGF-binding proteins associated with intrauterine growth restriction in fetal sheep during early and mid pregnancy. Ped. Res. 60:507-512.

Lea, R.G., P. Wooding, I. Stewart, L.T. Hannah, S. Morton, K. Wallace, R.P. Aitken, J.S. Milne, T.R. Regnault, R.V. Anthony and J.M. Wallace. 2007. The expression of ovine placental lactogen, StAR, progesterone associated steroidogenic enzymes in placentae of over-nourished growing adolescent ewes. Reproduction 133: 785-796.

Wright, C.D., R. J. Orbus, T.R.H. Regnault and R.V. Anthony. 2008. Effects of early gestation growth hormone administration on placental and fetal development in sheep. J. Endocrinol. 198:91-99.

Jeckel, K.M., S.W. Limesand and R.V. Anthony. 2009. Specificity protein-1 and -3 trans-activate the ovine placental lactogen gene promoter. Mol. Cell. Endocrinol. 307:118-124.

Jozwik, M., B. Pietrzycki, M. Jozwik and R.V. Anthony. 2009. Expression of enzymes regulating placental ammonia homeostasis in human fetal growth restricted pregnancies. Placenta 30:607-612.

Purcell, S.H. J.D. Cantlon, C.D. Wright, L.E. Henkes, G.E. Seidel, Jr. and R.V. Anthony. 2009. The involvement of proline-rich 15 in early conceptus development in sheep. Biol. Reprod. in press (Epub July 15, 2009).

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