Research
PKC
The PKC family of enzymes represents a diverse set of proteins with varying functions from the regulation of cellular proliferation, apoptosis, and necrosis. Work on this enzyme family was the first contribution of our lab to the field. Our lab generated isozyme specific modulators that allowed research to begin to separate the different functions of each isozyme. This work has led to the discovery of the opposing effects of PKCδ and PKCε in the mitochondria in the context of ischemic heart disease (heart attack).
For more details, see publication.
ALDH
The ALDH family of enzymes plays an important role in detoxifying aldehydes. Exposure to toxic aldehydes can come from cigarette smoking, drinking alcohol, exposure to formaldehyde, as well as from endogenous processes such as lipid peroxidation and amino acid metabolism. The ALDH enzyme family is made up of 19 isozymes in humans, each with specific substrates that they metabolize.
For more details, see publication.
Many of the isozymes have been associated with human disease, and known mutations found in the human population have been shown to cause decreased catalytic function lead to the accumulation of toxic aldehydes. Our lab has been working to develop small molecule modulators of ALDH activity that are isozyme specific. These modulators will enable researchers to distinguish the function of these different ALDH isozymes, and may be useful in treating human diseases caused by mutations in ALDH enzymes. Our compounds have been found to improve outcomes in cardiac disease in animal models.
Mitochondrial Dynamics in Normal and Diseased States
The mitochondria plays important roles in maintain the energy balance of the cell and mediating responses to stress. Part of the regulation of these functions is mediated by mitochondrial fission and fusion. The Drp1 and Fis1 proteins are key modulators of these processes, and bind to promote fission. Our lab has identified a peptide that selectively inhibits Drp1 in the mitochondria. We have shown that this can reduce excessive mitochondrial fission in the context of cardiac disease and Huntington’s disease, leading to improved outcomes.
For more details, see publication.
G6PD
Glucose-6-phosphate dehydrogenase (G6PD) is a key enzyme in the pentose phosphate pathway that generates NADPH and reduced glutathione (GSH). G6PD is essential in maintaining the redox equilibrium to handle oxidative stress, especially in erythrocytes.
Over 400 million people worldwide have G6PD deficiency resulting from point mutations in G6PD. There are over 160 known point mutations, which give symptoms ranging from chronic non-spherocytic hemolytic anemia (Class I) to almost no clinical manifestation (Class IV). Some mutations reduce catalytic activity, while other mutations reduce the stability of the enzyme without affecting the catalytic activity.G6PD functions as a dimer and a tetramer. In addition to the catalytic NADP+, G6PD also binds a second NADP+ far from the active site. Once the G6P substrate is bound, this structural NADP+ may migrate to the catalytic site. The structural NADP+ is essential for enzyme function, and many Class I mutations are found near the structural NADP+ site.
Our lab aims to find small molecules that correct G6PD mutations by increasing the catalytic activity and/or stability of the mutant enzyme. This project involves characterizing the stability and activity of mutant G6PD in vitro, in cell culture, and in vivo models. We plan on conducting a high-throughput screen to identify molecules that can correct G6PD mutations.