Vesicles and Signaling
Probing the Pathophysiology of ME/CFS through Proteomics and Metabolomics
One reason that many ME/CFS patients are unable to work is that their maximal ability to produce energy, measured by cardiopulmonary exercise testing (CPET), is extremely low. For many ME/CFS patients an increase in physical or mental activity results in an increase in symptoms termed post-exertional malaise. The cause of post-exertional malaise, like the cause of ME/CFS, is not understood, although it is one of the most debilitating symptoms of ME/CFS sufferers.
Our central hypothesis is that the study of post-exertional malaise provides an opportunity to obtain new insights into the etiology of ME/CFS. We will obtain samples from patients at several different time points, prior to an exercise challenge, when they are experiencing their usual levels of symptoms, and at a time of heightened symptoms, post exercise, enabling deeper insight into abnormal biological functioning associated with the disease.
By analyzing, in conjunction with physiological data, metabolites, circulating inflammatory molecules, and extracellular vesicle (EV) cargo in blood samples from before and after exercise sessions, we aim to uncover markers and mechanisms of post-exertional malaise in ME/CFS. Our broad survey of possible molecular responses to exercise will include inflammatory proteins and immunogenic mitochondrial DNA fragments, targeted and untargeted metabolomics of blood serum, and a detailed proteomic and metabolomic characterization of EVs. EVs are released into the circulation during exercise and could therefore contain biomarkers or contain cargo that plays an active role in mediating the abnormal response to physical activity in ME/CFS.
We expect to provide comprehensive data on metabolomic and proteomic changes associated with post-exertional malaise in ME/CFS that will enable identifications of previously unknown biomarkers and mechanisms associated with this disease.
Dr. Maureen Hanson will lead the project, which involves a collaboration with Dr. Frank Schroeder at the Boyce Thompson Institute, an expert in mass spectrometry and metabolomics, with Dr. Sheng Zhang, Director of the Cornell Proteomics and Mass Spectrometry Facility, and with Dr. Andrew Grimson, a microRNA expert. A key member of the team is Research Associate Dr. Ludovic Giloteaux, who will isolate and characterize extracellular vesicles and collaborate on analysis of their cargoes. Dr. Betsy Keller and Dr. Geoff Moore will analyze the physiological data obtained from subjects who provide blood before and after CPET from which the EVs will be obtained. Dr. Zhenglong Gu will examine the effect of exercise on release of plasma mitochondrial DNA. Dr. Avery August, who studies immune cell regulation, will assist in interpretation of the significance of EV protein cargo and inflammatory markers.