The focus of our research is the role of mitochondria and cellular metabolism in cardiovascular disease.
Characterization of cellular and mitochondrial iron regulation. Our lab has identified a novel mitochondrial protein, ATP-Binding Cassette-B8 (ABCB8), to play a role in mitochondrial iron homeostasis and mitochondrial iron export. We have generated mice with ABCB8 knockout in the heart and shown that these mice develop cardiomyopathy and mitochondrial iron accumulation. In addition, we have identified a novel pathway involving mTOR and tristetraprolin to regulate cellular iron homeostasis under iron-deprivation conditions. Current studies focus on further characterization of ABCB8 in iron homeostasis in other organs and other disorders, such as cancer and hematological disorders. We are also focusing on other potential mechanisms of cellular iron regulation.
Role of mitochondrial iron in doxorubicin-induced cardiomyopathy. Doxorubicin is an anti-cancer drug that also causes cardiomyopathy. The mechanism for the doxorubicin-induced cardiotoxicity is not known. We have shown that doxorubicin accumulates in the mitochondria and increases mitochondrial iron levels. Mice with overexpression of ABCB8 in their heart or treatment of animals with mitochondrial-permeable iron chelators protects against doxorubicin-induced cardiomyopathy, indicating a role for mitochondrial iron in the deleterious effects of doxorubicin. Current studies are on identification of novel mitochondrial-specific iron chelators and characterization of novel mechanisms that regulate mitochondrial iron homeostasis.
Functional characterization of sucrose nonfermenting-1 (SNF1) related kinase (SNRK). SNRK is a novel protein with sequence homology to AMP kinases. However, its function is not yet delineated. Our lab has shown that SNRK regulates cellular proliferation by inhibiting the beta-catenin pathway. We are currently studying the role of this protein in cardiac metabolism. We have generated a transgenic mouse that overexpresses the protein in the heart and are breeding knockout mice to generate more animals. Our studies indicate that SNRK improves cardiac efficiency and protects against ischemia-induced damage. We are also studying the role of SNRK in cancer metabolism.
Role of tristetraprolin (TTP) in cellular metabolism. TTP plays a role in cellular inflammatory response and we recently showed that it also plays a role in the regulation of iron conservation. We have mice with genetic knockout of TTP in the background of deletion of TNF recetor 1/2 (thus lacking the inflammatory process), which we are now using to study the role of this protein in iron deficiency response and cellular metabolism.
None of this work would have been possible without the hard work of the wonderful people of the lab.