Human Mesenchymal Stem Cells and the Epigenetic Programming of Obesity

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 DESCRIPTION (provided by applicant): Background: Obesity during pregnancy is increasingly recognized as an important contributor to obesity risk in the next generation. However, surprisingly little is known about how maternal obesity influences obesity risk for human babies. I am using primary, human mesenchymal stem cells (MSCs) derived from umbilical cord tissue of newborn babies to investigate how intrauterine exposures associated with mother's body size may contribute to increased obesity risk for her baby. Specifically, I will investigate whether intrauterine exposures alter the epigenetics of these umbilical cord cells to determine whether mothers' obesity contributes to disordered metabolism in her baby. Epigenetics refers to chemical changes in the DNA structure and function, such as DNA methylation, that can have long-term consequences for altered gene expression and subsequent cellular physiology. Candidate: I am an Assistant Professor in the Department of Pediatrics, at the University of Colorado School of Medicine. I am currently supported by an institutional NIH K12 award and am seeking to transition to an individual K01 award for the remaining 3 years of my training program. This includes advanced training in epigenetic bench science for the measurement of DNA methylation and large dataset biostatistical analyses for the interpretation of DNA methylation array and RNA sequencing datasets. The skills developed through this training program will be invaluable to my long-term career goal of understanding how obesity during pregnancy impacts the baby's risk for becoming obese. Environment: The University of Colorado School of Medicine is an excellent environment for obesity and fetal programming research. I have put together an exceptional team of senior scientists with strengths in fetal programming (Mentor Jacob Friedman, PhD), as well as epigenetics (Co-Mentor Ivana Yang, PhD) and biostatistics (Co-Mentor Katerina Kechris, PhD). Research: Based on my preliminary data, which establish the feasibility of the umbilical cord MSC model, I hypothesize that exposure to obesity during pregnancy alters how these cells become specialized for different cell types (i.e., fat or muscle), and that when these cells become muscle cells, results in epigenetic modifications leading to inflammation and insulin resistance. To address these hypotheses, I will use MSCs from babies of normal weight and obese mothers, along with corresponding DNA methylation array and gene expression datasets (RNA sequencing) to determine whether maternal obesity induces epigenetic modifications in offspring MSCs that subsequently affect 1) differentiation to fat or muscle cells, 2) muscle cell inflammation pathways, and 3) muscle cell insulin resistance. Identifying specific epigenetic modifications that are functionally relevant to MSC physiology will give critical insights into the fetal programming of obesity.