Rachel Jamison Perry, PhD

Project Title: Liver Calcium Regulation of Hepatic Gluconeogenesis in Pregnancy and in Neonates

Neonatal mortality is unacceptably high in many parts of the United States and the world. We observed that mice with a liver-specific knockout of a key mediator of the glucagon signaling cascade, inositol 1,4,5-triphosphate receptor subtype 1 (IP3R1) exhibit impaired gluconeogenesis in pregnant heterozygote mothers and in pups immediately after birth, and that approximately half of the IP3R1 KO pups that are born, die in the early hours after birth. This project tests the overarching hypothesis that by promoting gluconeogenesis and maintaining euglycemia required for the muscle function needed for suckling, IP3R1 action is required for the successful transition to breastfeeding. Relatedly, we hypothesize that liver-specific IP3R1 knockout mice exhibit impaired survival in the immediate neonatal period, as a result of their failure to maintain euglycemia due to impaired hepatic, but not renal, glucose production. The excess mortality, we believe, will be rescued by high-carbohydrate nutritional supplementation in pups whose behavior immediately after birth predicts that they are at high risk of neonatal mortality(predicted by an algorithm that will be validated in the work in this project). If successful, the experiments proposed in this application will identify IP3R1 as a new node in the mechanism by which glycemia is coordinated immediately after birth, and a new target to optimize the transition to breastfeeding.