Deconvoluting Signaling Activities of Mitochondrial-derived Reactive Metabolites with Unparalleled Depth and Spatiotemporal Precision

Mitochondria-derived reactive metabolites (mt-REMs) drive context-specific immunomodulatory behaviors during metabolic reprogramming. Yet, no method can interrogate the cause-and-effects of individual mt-REMs with locale specificity and temporal resolution. Mapping mt-REM-directed signaling changes with spatiotemporal resolution would thus be transformational. I will develop a spatiotemporally-resolved in-vivo mt-REM-responsivity-mapping technology. This cross-disciplinary innovation will enable localized build-up of an individual mt-REM in one specific cell type with precise temporal, dosage, and chemotype control. For the first time, I will map cell-type-specific “first responders”, proteins attuned to react with the specific mt-REM in an otherwise unperturbed system, in a manner that alters signaling across distinct disease contexts. My ability to assimilate chemical biology, organic/medicinal chemistry, & biotechnology enables me to achieve these goals leveraging functional mechanistic models principally zebrafish, mice, and cultured primary cells. The resulting new knowledge is biomedically important: my previous work on lipid-derived metabolites supports that we can leverage this information to design drug candidates. This research project promises transformative biomedical advances and technological breakthroughs with enormous potential for unveiling reactive metabolite-guided biological mechanisms influencing cell function & disease outcomes.