Project Summary
Plant (poly)phenolic compounds are widely acknowledged to have health benefits in humans, and diets high in
plant-based foods are associated with good health. Phenolic compounds can act as antioxidants, by scavenging
free radicals and preventing free radical formation, and can regulate metabolic reactions by binding to various
enzymes. Despite epidemiological evidence that these phytochemicals have health-promoting effects, the
mechanisms of action behind their bioactivity remain incompletely understood. The overarching goal of this
proposal is to elucidate the mechanisms underlying various biological activities of (poly)phenolic compounds
including antioxidant, anti-inflammatory, and other medicinal properties. The specific aims are 1) Systems-level
analysis of metabolism upon (poly)phenolic compound addition, 2) Exploring the effect of (poly)phenolic
compounds in cell lines and animals, and 3) Searching for synergy by paring (poly)phenols, small-molecule
drugs, and nutrient conditions.
The complexity and diversity of (poly)phenolic compounds and their biological
activities necessitate innovative analytical techniques for systems-level quantitation of metabolic effects.
The
proposed research will innovate i) a widely applicable method for mapping the mechanism of action of natural
products and ii) targeted uses of (poly)phenols as a sole preventive and therapeutic strategy and as a
complement to other drugs. To this end, a novel method, termed ‘shotgun metabolomics,’ will be developed.
Furthermore, a combination of state-of-the-art mass spectrometry, cleverly designed isotope tracing strategies,
and a fundamental thermodynamic principle will be used to obtain and integrate metabolomic, fluxomic, and
thermodynamic measurements across cellular metabolism. This integrative approach will expand the coverage
of quantitative metabolic analysis. Using this approach, this project will generate and test new hypotheses
regarding systemic metabolic rewiring, elicited by (poly)phenols, that contributes to preserving energetic
homeostasis in terms of ATP and redox molecules. The proposed systems-level analysis will reveal multi-faceted
effects of (poly)phenols on various parts of metabolism, which collectively contribute to cells’ ability to fight
stressors and maintain homeostasis. Exploring and elucidating the mechanisms underlying (poly)phenols’
biological activities will promote preventive and integrative health care.