Quantifying the impact of hyperglycemia on embryonic metabolism and development in C. elegans.

The objective of this project is to generate single cell resolution information about how metabolism changes at single cell resolution over the course of embryonic development in embryos from normal and hyperglycemic mothers. This is relevant to understanding why structural birth defects are 2-3 times more likely in pregnancies of diabetic mothers. We will use the nematode C. elegans as a model in our studies and since many aspects of development and metabolism are conserved, our findings will likely further our understanding how metabolism affects morphogenesis in vertebrate embryonic development and human structural birth defects. C. elegans is an excellent model because its simplicity and accessibility will enable us to fully characterize the cellular metabolism of individual cells during embryonic development and determine how hyperglycemia impacts cell fate specification and morphogenesis. Our preliminary data show that cellular metabolism varies across cells and across developmental time. We hypothesize that maternal hyperglycemia increases oxidative stress in embryonic cells, resulting in insufficient cellular energy for essential migrations and inducing AMPK-mediated chromatin changes that inhibit the expression of cell fate TFs, resulting in developmental defects. To test this hypothesis, we will use complimentary approaches of quantitative time-lapse imaging of biosensors, and transcriptomics plus metabolic modeling. We will integrate the results from each approach to create a single cell resolution profile of embryonic metabolism across developmental time in control and maternal hyperglycemia embryos. This will enable us to link developmental defects to disruptions in metabolism at the cellular level. This work will generate the first comprehensive metabolic atlas of a metazoan embryo with the single cell resolution across developmental time and determine how embryonic cellular metabolism and developmental processes are impacted by hyperglycemia. Project Number: 1R21HD117015-01A1 | Fiscal Year: 2025 | NIH Institute/Center: Eunice Kennedy Shriver National Institute of Child Health and Human Development (NICHD) | Principal Investigator: Amanda Zacharias | Institution: CINCINNATI CHILDRENS HOSP MED CTR, CINCINNATI, OH | Award Amount: $474,878 | Activity Code: R21 | Study Section: Special Emphasis Panel[ZRG1 CDB-E (02)] View on NIH RePORTER: https://reporter.nih.gov/project-details/1R21HD11701501A1