Ashley Solmonson, Ph.D.
Department Children’s Medical Center Research Institute at UT Southwestern
I have a broad interest in metabolism in disease including how aberrant metabolism can induce disease states and how targeting metabolic pathways can be therapeutically useful. I have experience at the level of chemical reactions all the way to a systems level metabolism of mammalian development. In graduate school, my research showed that altered mitochondrial metabolism driven by uncoupling proteins is sufficient to inhibit growth signaling and tumorigenesis. I also studied how cold exposure in mice leads to distinct temporal metabolism in various depots of white and brown adipose tissue. This experience introduced me to novel methods of metabolic research and led me to pursue a postdoc with a leader in the field of metabolism.
As a postdoctoral fellow in the lab of Ralph DeBerardinis, I was a member of the Genetic and Metabolic Disease Program (GMDP) at Children’s Research Institute. I focused on characterization of a new inborn error of metabolism, Lipoyltransferase I (LIPT1) deficiency. LIPT1 transfers lipoate, an essential co-factor, on to mitochondrial 2-ketoacid dehydrogenase enzymes like pyruvate dehydrogenase (PDH), alpha ketoglutarate dehydrogenase (αKGDH), branched chain ketoacid dehydrogenase (BCKADH). These target enzymes of LIPT1 are critical to central carbon and energy metabolism and LIPT1-deficiency induces dysfunction in these three enzymes simultaneously. Using advanced metabolic platforms, stable isotope labeling, cell culture, and mouse models, I have published a series of papers that have enlightened the impact of LIPT1 deficiency. First, we showed that LIPT1 deficiency alters the metabolic profile of patient plasma and fibroblasts and results in embryonic lethality in a mouse model harboring our patient’s novel mutation. We then showed that LIPT1 deficiency resulted in distinct molecular and metabolic perturbations relative to defects in the mitochondrial fatty acid synthesis pathway that is upstream of lipoate synthesis. Finally, I developed methods to perform stable isotope tracing in pregnant mice to probe the effects of LIPT1 dysfunction in the placenta and midgestation embryos. This led to the discovery that LIPT1 disrupts heart and brain development in the mouse consistent with what has been observed in patients. As well, we identified a LIPT1-dependent role in erythrogenesis and linked the patient’s chronic anemia phenotype with the LIPT1 deficiency diagnosis.
The techniques I developed also uncovered interesting observations related to healthy development during midgestation. We found that a metabolic transition occurs between gestational day 10 and 11, that the placenta and embryo respond differently to that transition, and that each compartment uses distinct strategies to meet the metabolic demands of energy production and biosynthesis. As well, fetal tissues like the brain, heart, and liver display distinct metabolic phenotypes as early as day 11 indicating that metabolism may play a more mechanistic role in organogenesis. Overall, the approach that I have developed puts me at the forefront of a resurgence of the developmental metabolism field and has me poised to discover new relationships between metabolism and mammalian development. Personally, I am interested in discovering ways in which the placenta balances its own growth and functions with the nutrient demands of the fetus.
My long-term goal is to run a successful research laboratory investigating the relationship between metabolism and pregnancy diseases. For the first 5 years, my laboratory will focus on projects related to the metabolic demands of placenta growth and how perturbing metabolism impacts placental development and function. We will investigate metabolic phenotypes of human placentas from pregnancy complications like preeclampsia, intrauterine growth restriction, and gestational diabetes to improve model systems related to characterizing these diseases. Ultimately, my laboratory will attempt to understand metabolic mechanisms of communication and cooperation between the maternal/adult, placenta, and fetal compartments during pregnancy.