DARK-PEP: Mapping the Human Peptidome: Genetic Variability and GPCR Signaling

Ziel

Peptide hormones are central regulators of human physiology, controlling processes from metabolism and appetite to stress and reproduction. They act mainly through G protein–coupled receptors (GPCRs), which are also key drug targets. Yet still 100 GPCRs remain “orphans” with no known endogenous activator. This highlights a major knowledge gap: undiscovered peptide hormones and receptor–ligand pairs likely exist but have eluded current detection methods. At the same time, genetic variability in peptide hormones themselves remains virtually unexplored, despite evidence that rare population variants in the receptors can alter signaling and physiological outcomes.

This project will chart the “dark matter” of human peptide signaling by combining computational, experimental, and genetic approaches. First, we will develop and fine-tune predictive models for peptide–GPCR interactions, trained on consolidated datasets at unprecedented scale, including a novel multiplexed receptor signaling assay. Second, we will apply these models to identify new bioactive peptides from novel unexplored sources, systematically testing them against the GPCR-ome. Third, we will map naturally occurring human variants in peptide hormones and assess their impact on signaling strength, bias, and selectivity, integrating individual-level genotype–phenotype associations from biobank-scale datasets to better inform rational peptide design with optimized pharmacological parameters.

By filling critical discovery and functional gaps, this project will expand the human endocrine landscape, uncover the genetic basis of inter-individual variation in hormone signaling, and establish a scalable computational and experimental framework for the rational design of next-generation peptide therapeutics.