Timothy M Crombleholme, M.D.
Director, Fetal Care Center of Dallas
Medical City Children’s Hospital
“Re-Programming the Fetus: Placental Gene Transfer of Insulin-like Growth Factor-1 in Intrauterine Growth Restriction”
Barker’s “thrifty hypothesis posited that the fetus is programmed during maternal starvation or intrauterine growth restriction (IUGR) to hold onto every nutrient with a 19 fold increase in obesity, diabetes, and cardiovascular disease in adulthood. Multiple growth factors have been found to be important to normal placental development and their deficiency has been implicated in the pathophysiology of IUGR. Among the most important of these is insulin-like growth factor-1 (IGF-1) which is deficient in human IUGR and every animal model of IUGR described. We developed the murine uterine artery ligation model (MUAL) of IUGR which we have shown replicates human IUGR in its effects on fetal growth and placental gene expression resulting in obese, diabetic adult mice with hypertensive cardiomyopathy. Intra-placental gene transfer of IGF-1 in the MUAL modal not only corrects fetal growth but reprograms the metabolic fate of the animal eliminating the predisposition to obesity, diabetes and hypertensive cardiomyopathy. IGF-1 drives the expansion of placental endothelial progenitor cells and fetal neovascularization of the placenta allowing greater placental nutrient and O2 transport not only correcting fetal growth but reprogramming metabolic fate as an adult. The cellular mechanisms by which these effects are mediated are linked to the nuclear factor kappa light chain enhancer of activated B cells (NF-KB) pathway, specifically via the IKB kinase alpha and beta (IKK-a- and IKK-b) and the mTOR pathway.
Thursday, May 3, 2018, 10:00AM-11:00PM, LIB-110
University of North Texas Health Science Center
Fort Worth, Texas