The major focus of our research is trace element biology and toxicology, and current projects address cadmium and iron.
Cadmium is an environmentally important toxic metal that adversely affects a number of cellular processes influencing both cell death and proliferation.
We are using cadmium as a tool to study linkages between signaling, cytoskeletal assembly, oxidative stress, oncogene expression, and apoptosis in renal mesangial cells.
Dependent on conditions of exposure, cadmium may enhance cell survival (potentially contributing to its carcinogenicity) or promote cell death by competing pathways of apoptotic and apoptosis-like cell death, autophagy, and necrosis.
Multiple signaling pathways are involved in these events, and a particular interest in our lab is the involvement of the calcium/calmodulin-dependent protein kinase, CaMK-II. Cadmium also initiates disassembly of the filamentous actin cytoskeleton in mesangial cells, and the underlying mechanisms, which involve CaMK-II along with fragmentation and translocation of gelsolin, are being elucidated.
This system is proving useful for studying the links between cell signaling, cytoskeletal dynamics, and cell death.
Another metal of interest is iron.
Iron overload occurs in patients with transfusion-dependent anemias, such as thalassemia major.
By studying mechanisms of iron transport and storage, we hope to learn more about the toxic effects of iron in the context of cardiac and hepatic fibrosis.
A current interest is in the ATP-hydrolyzing activity that we have found to be associated with iron regulatory protein 1 (IRP-1), and the consequent links to cellular energy metabolism.
IRP-1 switches between an RNA binding state, where it regulate translation of a number of transcripts involved in iron metabolism and cellular energy management, and an enzymatic state in which it displays cytosolic aconitase activity.
In its aconitase form, IRP-1 is potentially an important regulator of cytosolic citrate levels, which tend to be high in cancer cells. IRP-1’s role in diverting citrate to fatty acid synthesis for new membranes on the one hand, and glutamate production on the other hand, is currently under investigation.