Research

How do metabolites function as signaling molecules independent of their metabolic pathways? 

Metabolites and other small molecules often accumulate during diseases such as cancer, infection, and inflammation.  Their roles as metabolic substrates have been studied for over a century, yet their non-metabolic functions are largely unexplored. We propose that, independent of their metabolic reactions and pathways, metabolites have unexplored yet critical functions as allosteric signaling molecules in cancer and other diseases. Using questions guided by human patient data, we conduct hypothesis-driven research through a combination of cell-based, in vitro, and ultimately in vivo models.  We collaborate with biochemists, structural biologists, and other experts to develop new methods to study protein–metabolite interactions.

Allosteric regulation of mitochondria metabolism and innate immune signaling. 

Lactate is the second most abundant circulating carbon and is often elevated in cancer and other diseases.  While most studies focus on its known metabolic functions, we recently found that lactate is also a mitochondrial signaling molecule.  Using a combination of genetic CRISPR screening, protein mass spectrometry, cell biology and biochemical approaches, we are dissecting the mechanisms by which lactate and other monocarboxylates signal to the mitochondria.  

Metabolic signaling as a regulator of cell fate decision.

Infectious and commensal bacteria collectively outnumber host cells.  They produce metabolites that are typically not metabolized by the host.  We hypothesize that these small molecules serve essential signaling functions, either as pro-inflammatory or disease tolerance molecules, and can provide insight into how small molecule signals alter protein functions in general.  We are using in vitro and in vivo systems to characterize the signaling functions of bacterial metabolites in cell proliferation, differentiation, and signaling.