Project Summary: Overall Despite the enormous suffering endured by millions of people worldwide, the underlying causes of Myalgic Encephalomyelitis/Chronic Fatigue Syndrome (ME/CFS) are unknown and effective therapies are lacking. ME/CFS is characterized by debilitating fatigue, musculoskeletal pain, headaches, cognitive difficulties orthostatic intolerance, and sleep disturbances. The absence of simple objective tests prevents many from obtaining an appropriate diagnosis and inhibits drug development because of the lack of biomarkers to monitor the efficacy of experimental therapies. In order to gain fundamental mechanistic insights into ME/CFS, we will leverage the experience, capabilities and varied backgrounds of researchers from four different colleges at Cornell University, Florida Atlantic University, the Hospital for Special Surgery, and an ME/CFS expert physician. We will take advantage of an enormous amount of data already obtained from patients and controls both before and after symptom provocation through exercise, as well as a valuable set of new samples. Three research projects will seek to (1) use cutting-edge multi-omic single cell profiling to examine alterations in cell types, gene expression, and cell-cell interactions that occur in ME/CFS muscle (Project 1), (2) identify tissue injured in ME/CFS following exercise through characterization of RNA released into circulation and (3) identify the RNA and protein cargo of extracellular vesicles in ME/CFS patients that may alter function of target cells (Project 2) and (4) Use genomic and computational methods to better understand the gene regulatory mechanisms that result in immune dysregulation in ME/CFS and systematically identify ME/CFS-specific alterations in signaling across the immune system (Project 3). These three research projects are supported by a Research Core that will act as a resource for genomics technology expertise, reagents, and services and for data management and integrated analysis. Multi-omic analysis and predictive modeling carried out in all three Projects will provide a foundation for future development of therapeutics and diagnostic tests. All Center activities will be coordinated through an Administrative Core, which will foster synergy and integration within the Center, while also being the platform for collaboration with other ME/CFS Collaborative Research Centers, a Patient/Advocate/Caregiver Committee, other ME/CFS researchers, and the Data Management Coordinating Center. The Administrative Core will also be responsible for outreach activities that are designed to increase awareness and understanding of ME/CFS within the research community, health professionals, and the general public, and will administer a pilot project program designed to bring new ideas and researchers into the ME/CFS field.

Project Narrative Myalgic encephalomyelitis/chronic fatigue syndrome (ME/CFS) is a serious, debilitating illness whose molecular basis is not understood, preventing development of simple diagnostic tests and endpoints for evaluating therapies in clinical trials. This Center will bring together a multidisciplinary team with expertise in immunology, muscle biology, gene expression, cell-free RNA, extracellular vesicles, plasma protein characterization, and computational analysis of large data sets. By assessing biospecimens from subjects at baseline and following symptom exacerbation, the team will seek to understand the underlying pathophysiology of ME/CFS and enhance knowledge of the lay public, patients, and health professionals concerning the disease.