We are interested in the redox determinants of normal and abnormal blood vessel function and phenotype. Our specific focus has been on nitric oxide as an endothelial product that is susceptible to oxidative inactivation, the thiol proteome and its oxidative posttranslational modification, and the molecular responses of the endothelial cell to hypoxia.
Nitric oxide is a free radical that reacts readily with a variety of molecules in the vascular milieu to effect its biologic actions. Chief among these are molecules bearing thiol functionalities which, in the presence of molecular oxygen, lead to the formation of S-nitrosothiols or thionitrites. The unique biologic actions of these naturally occurring nitric oxide adducts have served as a major focus of the laboratory's research efforts. Both low-molecular-weight and protein thiols react with nitric oxide to form the corresponding S-nitrosothiols; modification of protein thiols in this manner represents a form of post-translational modification that alters protein function and cell phenotype.
Cell redox state is a critical determinant of cell phenotype, especially in the setting of hypoxia. We have demonstrated the importance of key microRNAs induced by hypoxia that govern changes in the endothelial metabolome and metabolic phenotype, chief among which is mir210. This microRNA appears to regulate the conversion from oxidative phosphorylation to anaerobic glycolysis (the Pasteur effect), and to limit the cytotoxic production of mitochondrial reactive oxygen species. In metabolomic studies of hypoxic cells, we have also found that the unique derivative of 2-oxoglutarate, L-2-hydroxyglutarate, accumulates to suppress glycolysis and shunt glucose to the hexose monophosphate shunt in order to facilitate elimination of the growing pool of reactive oxygen species in this setting. These studies have been facilitated by the development of unique fluorescent sensor proteins that monitor NAD(P)+ and NAD(P)H in living cells in different cellular compartments.
Another focus of the laboratory is in the newly developed field of network medicine, which represents the marriage of systems biology and network science. Among our recent contributions to this field are included the identification of disease-specific modules or subnetworks in the comprehensive human protein-protein interactome, the identification of the modules regulating endophenotypes common to many diseases (inflammation, thrombosis, fibrosis), the creation of a combinatorial method for the development of rational polypharmacy in the treatment of disease phenotypes, and the use of network proximity of specific drug targets within the protein-protein interactome to repurpose approved drugs. These approaches help redefine human diseases in comprehensive molecular terms, permit the identification of overlapping pathways governing diseases not previously recognized as having common underlying mechanisms, and facilitate the identification of potential drug targets or pathways for therapeutic purposes.
NRB, Room 630
77 Avenue Louis Pasteur
Boston, MA 02115