Description of Research Expertise

The two major research interests of the Mesaros group include quantitatively understanding the pathological metabolic changes in Friedreich’s Ataxia (FRDA) and biomarkers of exposure and exposure-response to major pollutants.

1. Quantify and achieve a targetable understanding of how lipid metabolism is disrupted as a consequence of mitochondrial dysfunction in Friedreich’s ataxia (FRDA). FRDA is an autosomal recessive disease caused by an intronic GAA triplet expansion in the FXN gene, leading to reduced expression of the mitochondrial protein frataxin. Currently there is no approved therapy for FRDA. Individuals with FRDA exhibit neurodegeneration and hypertrophic cardiomyopathy is the cause of death in most cases. Lipid accumulation has been reported in heart tissues from FRDA patients and we quantified clear lipid accumulation in FRDA fibroblast (J Lipid Res. 2022 Sep;63(9):100255.) and in iPSC derived cardiomyocytes (CM) after FRX knock down (https://doi.org/10.1101/2022.09.27.22280432). The cardiomyopathy of FRDA exhibits distinctive pathological features, including a striking proliferation of mitochondria within the CM. In platelets from FRDA patients, decreased conversion of glucose to acetyl-CoA has been observed and is consistent with diminished pyruvate oxidation that we found in FRDA fibroblasts. To investigate if the findings in platelets reflect a therapeutically useful homeostatic mechanism- to reduce fat accumulation as well as to circumvent reduced glycolysis, we measured changes in the lipidome and metabolome in FRDA plasma and whole blood, to gain insights into the disease pathogenesis and identify potential biomarkers of FRDA onset, disease progression, and therapeutic intervention.

2. Measure the relationship between biomarkers of exposure and biomarkers of response from major pollutants. Biomarkers of exposure reflect the dose and timing of exposure to environmental pollutants and biomarkers of response capture the reaction of a living organism to this exposure. With new analytical chemistry approaches, understanding both of these types of biomarkers can better pinpoint the burden and mechanism of environmental contribution to disease and help untangle the complicated interaction of genetics and environment. Due to compelling preliminary evidence, we are interested in the potential involvement of toxicants in the pathological development of gestational diabetes. Recent studies show that pancreatic serotonin signaling plays a critical role in maternal glucose homeostasis. Epidemiological findings have linked PFOA exposure to maternal hyperglycemia, insulin resistance, and glucose intolerance. PFOA exposure in pregnant mice is causatively linked to gestational diabetes through mechanisms that perturb serotonin metabolism in the maternal pancreatic islets and the effects are modulated by genetic differences in vitamin B6 metabolism. We are investigating the serotonin pathway in PFOA-exposed mice to further elucidate the mode of action of this compound and identify pharmacologically relevant steps to design interventions. This project is a collaboration with Susiarjo Lab from the University of Rochester.

We are always looking for scientifically curious individuals with diverse background and expertise, to join our group! Please email your research statement pages and your CV to mesaros@upenn.edu

Description of Other Expertise

In addition to her own interests, Dr. Mesaros is the Director of the Translational Biomarker Core (TBC) within the Center of Excellence in Environmental Toxicology (CEET) at the University of Pennsylvania. Both her independent research and Director position entail maintaining a fleet of liquid chromatography-mass spectrometry, inductively coupled plasma-mass spectrometry, and high-resolution mass spectrometry instruments as well as training and supervising of support staff, undergraduates, graduate students, and postgraduate scientists.