Research in the Franco lab focuses on the study of the role of oxidants and oxidized molecules in disorders of the nervous system. In conditions of chronic inflammation such as those present in neurodegeneration and in tumors and their microenvironment, the powerful oxidant peroxynitrite is produced in the affected cells/tissue. Peroxynitrite production leads to the oxidative modification of tyrosine residues in proteins to form nitrotyrosine. Nitration can have a profound impact on protein activity by inactivating or activating a protein, or even inducing a new function that the normal protein cannot perform. Developing and applying multiple complementary methodologies, we showed that nitrated proteins play relevant roles in disease processes. We take a systematic approach to the study of nitrated proteins in neurological disorders: 1) we identify nitrated proteins with a “disease-driving” function, a function that is relevant to the disease process; we then 2) elucidate their mechanism of action; and 3) determine how nitration changes protein structure. We then integrate this information to find drugs that selectively bind to the modified structure of the nitrated protein and effectively inhibit the disease-driving function while sparing the function of the normal protein. Because nitrated proteins are found in conditions of acute or chronic inflammation, in the cells/tissues affected by the disease but not in normal cells, we believe these drugs should have minimal to no side effects.
o 2022. Jandy et al. “Peroxynitrite Nitration of Tyr 56 in Hsp90 induces PC12 cell death through P2X7R-dependent PTEN activation”. Redox Biology. 50:102247.
o 2019. Pestoni et al. “Peroxynitrite supports a metabolic reprogramming in merlin-deficient Schwann cells and promotes cell survival.” Journal of Biological Chemistry. 294(30):11354-11368
o 2019. Strayer, et al. “Ligand-independent activation of the P2X7 receptor by Hsp90 inhibition stimulates motor neuron apoptosis.” Experimental Biology and Medicine. 244(11):901-914.