Multi omics mapping of exercise-induced interorgan communication

Project Summary Exercise offers profound systemic benefits, leveraging multiple molecular pathways and mechanisms to enhance health. Exercise interventions have been shown to improve symptoms in cancer, cardiovascular diseases, and neurodegenerative disorders. Molecular mechanisms of exercise in disease prevention and reversal include anti-inflammatory effects and improved immune function, hormonal regulation, reduction of oxidative stress, and improved metabolic function. There is a growing body of literature on the individual pathways activated by exercise in specific disease cases, but a comprehensive investigation across the whole body is needed to identify pathways and molecules of interest to mediating the systemic benefits of exercise and complex interorgan communication. The Molecular Transducers of Physical Activity Consortium (MoTrPAC) has generated an invaluable resource for identifying molecular changes in response to exercise. We will leverage their exercised rat profiling (naive, 1, 2, 4, 8 weeks post treadmill). This dataset is unique in being multi-modal and multi-organ allowing us to capture the broadest repertoire of exerkines and co-profile the expression of their receptors within the same organ and across organs. We will compare these findings to profiles from healthy (GTEx and HuBMAP) and diseased (including HTAN and psychENCODE) humans. We propose to define a comprehensive, multi-organ catalog of exerkines. Using public databases, we will pair the exerkines with their receptors when known, revealing the whole-body landscape of exercise-induced signaling. For each organ, we will cross-reference the exerkine and receptor molecules with the relevant diseased and healthy human dataset to uncover overlapping pathways between disease dysregulation and exercise modulation. We will bioinformatically simulate single-cell expression data to predict exerkine and receptor cell types, and further predict cell-cell interactions, validating candidate receptor ligand interactions by spatial omics assays in the healthy and cancerous human intestine. We will: Aim 1. Generate and identify exerkines and receptors for 17 organs in MoTrPAC. Aim 2. Decode exerkines and receptors inter- and intracellular signaling events and synergistic cell-cell communication Aim 3. Analyze response of exerkines to disease in humans