Electronic Thesis and Dissertation Repository

Degree

Master of Science

Program

Biochemistry

Supervisor

Dr. Madhulika Gupta

Abstract

In this study, we explore the molecular mechanisms linking amino acid (leucine) deprivation to IGFBP-1 hyperphosphorylation in vitro. During pregnancy, a maladaptive fetal response to in utero amino acid deprivation leads to Fetal Growth Restriction (FGR). FGR infants display elevated phosphorylated IGFBP-1, which is associated with decreased IGF-I bioavailability. Leucine deprivation inhibits mechanistic target of rapamycin (mTOR) signaling and stimulates the amino acid response (AAR). Using HepG2 cells, a model for fetal hepatocytes, we demonstrate that in leucine deprivation, the AAR modulates total and phosphorylated IGFBP-1 while mTOR mediates total IGFBP-1 secretion only. We also reveal that protein kinases CK2 and PKC mediate IGFBP-1 phosphorylation and subsequent IGF-I bioactivity in leucine deprivation. Together, our findings implicate fetal hepatic AAR and CK2 activation as key mechanistic links between amino acid deprivation and decreased IGF-I bioavailability in FGR and suggest a novel role for PKC in modulating IGFBP-1 phosphorylation in vitro.