The three major research interests of the Mesaros group include quantitatively understanding the pathological metabolic changes in Friedreich’s Ataxia (FA), the changes in the critical fats (called lipids) in neurodegeneration, 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 (FA).
FA 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. Interestingly, we have observed increased fatty acid oxidation in platelets from patients with FA, but lipid accumulation has been reported in other tissues. 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 measure changes in lipidome and metabolome in FA fibroblasts and whole blood to gain insight into the disease pathogenesis and identify potential biomarkers of FA onset, disease progression, and therapeutic intervention.

2. Quantify the “sphingo-lipidome” changes that result from complex I inhibition by pesticides.
The etiology of most neurodegenerative disorders (ND) is multifactorial and consists of an interaction between environmental factors and genetic predisposition, but there is substantial evidence linking many ND to long-term/low-dose exposure to certain classes of pesticides. Most of these pesticides share the ability to induce mitochondrial dysfunction, oxidative stress, and other factors that are likely to lead to selective cell death. It is unlikely that oxidative stress is the sole factor that links mitochondrial dysfunction with neurodegeneration; therefore, defects in mitochondrial metabolism apart from ROS production could be important to the pathogenesis of several ND. This project measures the sphingo-lipidome perturbations caused by pesticides using primary rat neurons (RPN) and will expand our current understanding of mitochondrial abnormalities that result from complex I inhibition.

3. 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.
Description of Other Expertise
In addition to her own interests, Dr. Mesaros is the Technical Director of the Translational Biomarker Core 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.