The Oregon Health & Science University (OHSU) Precision Medicine Innovation Co-Laboratory (PMedIC) Innovation Grant was offered for a second year to support joint collaborative pilot projects between OHSU and Pacific Northwest National Laboratory (PNNL) researchers, as part of the formal partnership called PMedIC. For 2023, two awards of $50K each were funded.
OHSU Researcher Alina Maloyan, PhD, and PNNL Senior Scientist Thomas Metz, PhD, will work in collaboration to study the metabolism of myeloid cells in the offspring of obese mothers to detect metabolic changes in myeloid cells caused by intrauterine exposure to maternal obesity. We know that three out of ten women in the United States are obese prior to becoming pregnant. We also know that children born to obese women are programmed to become obese and develop metabolic diseases in adult life despite their own lifestyle choices. This means that the worldwide epidemic of obesity and metabolic diseases is not only a result of a sedentary lifestyle or poor diet but is also a consequence of a developmental program that is switched on by the intrauterine environment in obese women. This major public health issue motivated us to do this project.
The history behind this project started with the observation that obese mothers program their offspring to also become obese and metabolically unhealthy, a phenomenon called developmental programming. The mechanisms of this programming remain unclear, and no therapy exists that can reliably reverse it. Data from the researchers' laboratory and others show that obesity in pregnancy leads to immune dysfunction in obese mothers and their offspring. The team also has evidence from a mouse model that not only the percentage of immune cells but also their metabolism have changed. They found significant metabolic perturbations in the bone marrow cells of newly weaned offspring of dams on a high-fat diet. Similar metabolic changes were previously reported in aging mice. Based on these data, the team wanted to focus their studies on metabolic changes occurring within immune cells as a result of exposure to maternal obesity.
In this project, Dr. Maloyan and Dr. Metz will utilize the state-of-the-art metabolomics capabilities at PNNL to detect metabolic changes in myeloid cells caused by intrauterine exposure to maternal obesity. Findings from this analysis will provide preliminary data for future grant applications:
OHSU researchers Brian Scottoline, MD, PhD; Jamie Lo, MD; Adam Crosland, MD, MPH; and Lyndsey Shorey-Kendrick, PhD, will investigate how the metabolome of amniotic fluid changes during gestation in collaboration with Chaevien Clendinen, PhD, an analytical chemist at PNNL. This pilot study is a necessary first step before using these data as a reference for larger collaborative grants to determine the impact of adverse maternal exposures on amniotic fluid composition and fetal development and outcomes and to identify the underlying mechanisms and pathways involved. The in-utero environment is comprised of the placenta and amniotic fluid. However, there has been little research performed on amniotic fluid. If successful, this study will result in knowledge gained regarding normal amniotic fluid composition that can be used with current and future non-human primate models of an adverse maternal in-utero environment to interrogate the impact of environmental perturbations on amniotic fluid composition.
There has been a lot of attention given to the placenta to better understand the in-utero environment and how it influences fetal development and offspring outcomes because it is more readily accessible. However, these placental studies are performed at the end of the pregnancy. This project is the first study to examine the chronological changes in amniotic fluid across pregnancy to understand how they influence fetal development and outcomes. Existing cross-sectional studies examining amniotic fluid obtained at one timepoint in pregnancy suggest a key role of amniotic fluid in influencing fetal development. Serial amniotic fluid sampling across gestation has never been performed before in both human and animal models, until now.
The short-term goal of this project is that this rhesus macaque amniotic fluid metabolomics data will be integrated with other amniotic fluid omics data (proteomics, lipidomics, and glycomics) and then linked to existing longitudinal fetal biometry and Doppler ultrasound data and placental and fetal brain magnetic resonance imaging (MRI) results from the same pregnancies to gain insight into how control amniotic fluid composition changes in relation to normal fetal growth and development. The longer-term goal of this project is to use amniotic fluid collected mid-gestation to create a biological fluid or nutritional medium for preterm infants that have immature gastrointestinal tracts as a "preterm" form of breastmilk.
Success for this project includes the ability to: