Current Pilot Project Awardees

Project Title: Changes in gene expression in metabolic pathways found in the maternal organs of mice that lactated provides a protective advantage to the mother.

Recent studies have suggested that lactation significantly lowers the risk of developing T2D by almost 50% and a strong inverse relationship exists between nursing and acquiring MASLD later in life. Despite these benefits from lactating, very little is known about the mechanism(s) that may explain how milk production exerts durable positive changes in maternal metabolism. Our initial hypothesis is that lactation alters the metabolism of maternal organs that persists past lactation and improves maternal metabolic health. We previously examined whether lactation protects against diabetes by improving maternal glucose metabolism in age-matched cohorts of C57Bl/6 mice that had lactated, did not lactate but went through a pregnancy, and age-matched virgins served as controls. Of note, mice that had lactated had reduced body fat compared to nulliparous mice. Additionally, liver size was increased and there was reduced liver triglycerides in mice that lactated. In the pancreas we saw an increase in islet size and insulin levels in mice that lactated. As an unbiased approach to examine the metabolic differences in lactation, no-lactation, and nulliparous mouse groups, we will perform RNA-seq and miRNA profiling on maternal organs to globally determine which metabolic pathways are affected. We will use bioinformatic programs and databases to map out changes in gene expression to metabolic pathways. We will integrate the differentially expressed miRNAs into metabolic pathways by identifying gene targets and then analyzing gene enrichment. The findings from this project will provide the necessary preliminary data to rigorously examine the impact of lactation on maternal metabolism in a rodent model and provide clearer metabolic targets to examine further in humans.

Project Title: Elucidating disease mechanisms of dengue virus infection in a humanized liver

Dengue, a viral infection transmitted through the bite of infected mosquitoes, can cause severe disease in humans including severe liver damage such as acute liver failure (ALF) and chronic liver damage (CLD). Dengue virus has four major serotypes. Dengue virus infections are unique in that pre-existing immunity to a serotype can enhance disease against a distinct serotype in a secondary infection, likely because of a phenomenon known as antibody dependent enhancement (ADE). Patients with pre-existing dengue immunity that are infected with a distinct dengue virus serotype from their first infection can develop in severe disease including dengue hemorrhagic fever (DHF) and dengue shock syndrome (DSS). Children who develop DHF and DSS are more likely to present with severe liver disease and ALF. We define dengue virus liver pathogenesis in two complementary humanized mouse models to determine the relative contribution of human macrophage and hepatocytes to acute liver damage in the context of dengue infection. Our mechanistic studies of dengue infection in the liver will reveal new therapeutic targets to mitigate the impact of dengue-mediated ALF and chronic liver inflammation.

Project Title: Elucidating disease mechanisms of dengue virus infection in a humanized liver

Dengue, a viral infection transmitted through the bite of infected mosquitoes, can cause severe disease in humans including severe liver damage such as acute liver failure (ALF) and chronic liver damage (CLD). Dengue virus has four major serotypes. Dengue virus infections are unique in that pre-existing immunity to a serotype can enhance disease against a distinct serotype in a secondary infection, likely because of a phenomenon known as antibody dependent enhancement (ADE). Patients with pre-existing dengue immunity that are infected with a distinct dengue virus serotype from their first infection can develop in severe disease including dengue hemorrhagic fever (DHF) and dengue shock syndrome (DSS). Children who develop DHF and DSS are more likely to present with severe liver disease and ALF. We define dengue virus liver pathogenesis in two complementary humanized mouse models to determine the relative contribution of human macrophage and hepatocytes to acute liver damage in the context of dengue infection. Our mechanistic studies of dengue infection in the liver will reveal new therapeutic targets to mitigate the impact of dengue-mediated ALF and chronic liver inflammation.

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.

Project Title: Altered nuclear calcium (Ca2+) in hepatocytes as a driver of chronic liver disease

Chronic liver disease affects a billion people worldwide and often results in cirrhosis. Although a variety of liver diseases can result in cirrhosis, a unifying feature is that the liver’s ability to repair itself and regenerate is impaired. Disruptions in nuclear calcium (Ca2+) signaling in hepatocytes have been identified as a critical factor influencing liver regeneration and fibrosis. Our group has demonstrated that loss of type II inositol 1,4,5-trisphosphate receptor (ITPR2), the predominant Ca2+ release channel in hepatocytes, impairs nuclear Ca2+ signaling, cell proliferation, and liver regeneration. Furthermore, ITPR2 is absent in hepatocytes from patients with chronic liver disease. This suggests that the loss of ITPR2 in hepatocytes is a common feature of chronic liver disease leading to cirrhosis, raising questions on how ITPR2 is important for nuclear Ca2+-mediated proliferation and liver regeneration. Existing evidence highlights the importance of intranuclear Ca2+ and b-catenin translocation into the nucleus, which is crucial for liver regeneration. Our preliminary data indicate that nuclear b-catenin levels decrease alongside reduced intranuclear ITPR2 and diminished nuclear Ca2+ signaling in hepatocytes from a metabolic dysfunction-associated steatohepatitis (MASH) mouse model. The hypothesis of this project is that ITPR2 in the nucleus is essential for generating intranuclear Ca2+ and facilitating b-catenin’s entry into the nucleus to drive liver regeneration. This project aims to investigate the role of nuclear ITPR2-mediated Ca2+ signaling in regulating β-catenin’s entry into the nucleus and to determine how ITPR2 localizes in the nucleus of hepatocytes to regulate nuclear Ca2+ signaling. This work will identify mechanisms that preserve liver regeneration despite chronic inflammation, providing new insights for the development of therapeutic strategies for chronic liver disease.