Grant: Discovery Grants Program - Individual

During pregnancy, appropriate placental metabolism is essential for fetuses to reach their growth potential; however, metabolic mechanisms during pregnancy remain poorly understood. I propose to develop a methodology to study fetal brain and placental metabolism using high-resolution magic angle spinning (HRMAS) magnetic resonance spectroscopy (MRS) in experimental mice. The mouse is the ideal pregnancy model to answer questions about metabolism because of the similarities between mouse and human fetal brain development and placental structure. While the results of 1H MRS studies in human pregnancy have been hampered by low signal sensitivity and low spectral resolution, there have been some intriguing findings. Here, the use of a high field magnet (600 MHz) combined with HRMAS will significantly improve our ability to measure known and novel metabolites in healthy fetal brain and placental tissue. HRMAS MRS of intact samples provides information about the location of metabolites in the tissue and, because it is non-destructive, allows the samples to subsequently be studied by other techniques to extract complementary cellular level information. The use of HRMAS MRS to study tissue biopsy samples from adult brain and other organs shows the tremendous promise of using this technique to study pregnancy. To date, the potential for MRS in mouse models of pregnancy has yet to be explored. Our first goal will be to establish the best way to collect tissue samples and to optimize the MR scan conditions to minimize changes to the tissue composition. We will then use this methodology to look at nuclei that are of high abundance in biological tissue such as 13C and 31P to provide a more complete metabolic profile of the tissue. Using innovative NMR experiments and data analysis such as the measurement of nuclear relaxation rates and unsupervised clustering analysis, we will aim to enhance the specificity and sensitivity of the MRS data by including quantitative NMR properties. Our study will include both male and female fetuses, allowing us to detect sex dependent effects. We will also look at whether there are differences in metabolite profile between different areas of the brain and placenta. Determination of the levels of brain and placental metabolites in healthy pregnancy and how they change throughout gestation is critical for understanding brain and placental function. This work will offer novel approaches for studying metabolism during pregnancy and, because MRS can be performed in utero, the basic research findings of this proposal can be translated to humans. Magnetic resonance imaging is routinely being used in pregnancy and the results of this study will provide a significant benefit to women's and fetal health through a better understanding of metabolism. This work will open avenues for potential diagnostics for early detection of metabolic abnormalities associated with pregnancy and monitoring of novel therapies.