Molecular and bioenergetic dynamics of in utero chronic hypoxia on placenta and brain

PROJECT SUMMARY Insufficiency of the placenta due to conditions such as hypertension, diabetes, and fetal congenital heart disease can lead to chronic in utero hypoxia. Chronic hypoxia increases the risk of neurodevelopmental disorders by disrupting the "placenta-brain" axis. Furthermore, the effects of chronic hypoxia on the developing

brain include disrupted energy metabolism and epigenome disruption, also called the metabolic-epigenetic axis. Rodent models of prenatal hypoxia are useful for studying the complex relationship between the placenta, brain, and epigenome. We developed 4D in utero Oxy-wavelet MRI (4D-uMRI) technology for simultaneous structural and temporal

mitochondrial dynamics assessment. We applied this technique to elucidate the variable metabolic dynamics of multiple models of prenatal injury. We have additional expertise in modeling prenatal brain injury and analyzing the effects of injury on the molecular phenotype of the developing brain through single nucleus multi-omics.

In this proposal, we will leverage our combined expertise to study the effects of chronic hypoxia on the placenta, brain, and epigenome. Our team has expertise in neuroscience, imaging, pathology, and placental biology. This study allows us to derive a comprehensive understanding of the correlation between metabolic

profiling and molecular phenotype. We will compare normoxic litters to animals exposed to 11% inspired oxygen from embryonic day 14.5 to 17.5. In Aim 1, we will use 4D-uMRI studies to determine to examine the relationship between placental structural anomalies and brain structural and metabolic dysfunction from

chronic hypoxia. The study will provide insight into whether there is a direct relationship between the extent of placental insufficiency and brain metabolic disruption and growth parameters. In Aim 2, we will assess the brain's metabolic response to hypoxia to test the relationship between the extent of metabolic dysfunction and

disruption of the transcriptome and epigenome through single nucleus multi-omic sequencing. The study proposes an innovative approach to testing the correlation between the extent of metabolic disruption and molecular phenotype. Together, these experiments will allow us to recognize novel correlations between

structure, function, and molecular disruption to discover novel targets for treating the neurodevelopmental deficits from chronic hypoxic brain injury.