Mapping inter-organ communication with new technologies - PROJECT SUMMARY Hormones, cytokines, and growth factors are essential signaling proteins in blood circulation that coordinate multi-organ functions to maintain physiological homeostasis. These “inter-organ” factors (e.g. Insulin) have inspired widely used therapeutics and biomarkers for diabetes, obesity (e.g. semaglutide), and cancer, owing to their systemic effects and accessibility in the blood. Despite decades of research, our understanding of the body’s inter-organ communication network remains limited. In contrast to systematic efforts to map the brain connectome, comprehensive mapping of inter-organ communication under both normal and disease conditions has lagged behind. This slow progress stems from the challenging qualities and complex roles of inter-organ factors, including their low abundance in the blood, regulated secretion, non-cell-autonomous functions, ligand- receptor binding, and distinct origin and target tissues. High-throughput approaches such as proteomics and transcriptomics struggle to capture this complexity, so most of our knowledge comes from laborious and unsystematic discovery efforts. This project will overcome these barriers by integrating state-of-the-art experimental and computational techniques to map inter-organ proteins in the blood. We will (1) identify and study inter-organ factors from our prior dataset of organ-secreted proteins, (2) identify disease-induced secreted proteins that influence pathology, (3) develop “receive-ome” tools to identify the tissue targets of circulating proteins, and (4) adapt AI-based tools to predict hormones and their receptors. These independent projects allow discoveries to be cross-validated across aims, increasing confidence in the results. In vivo experiments will be initially performed using Drosophila, an ideal model due to its conserved organ and endocrine systems, and then followed up in zebrafish and mice. Computational analysis will directly utilize human datasets. Our preliminary results demonstrate the feasibility of the proposed aims, leading our group to study novel circulating factors influencing body size and synaptic function. As technologies in the field evolve, we will expand to other signaling molecules including lipids and exosomes, as well as extracellular fluids such as cerebrospinal fluid (CSF). We will disseminate a variety of resources and datasets, including plasmids, transgenic animals, and detailed visualizations of inter-organ signaling networks. These resources will broadly benefit researchers investigating inter-organ communication, as well as those studying local cell-to-cell signaling and protein-protein interactions. Through these holistic efforts, we expect to find novel inter-organ ligands and receptors, unexpected tissue sources of circulating proteins, and potential targets for diagnostic markers and therapeutics.
