Project 1: Transcriptional mechanisms of ischemic diseases

The mammalian forkhead transcription factor O sub-family consists of FoxO1, FoxO3, FoxO4, and FoxO6. FoxO proteins are involved in a variety of cellular processes, including immune cell homeostasis, cytokine production, anti-oxidative stress, and cell proliferation and differentiation. While a majority of studies in the field have investigated FoxO1 and FoxO3, my lab has focused on FoxO4.

We have made several key contributions to the field. Most importantly, we have demonstrated that FoxO4 has specific and non-redundant functions from those of FoxO1 and FoxO3. The transcriptional activity of FoxO4 is cell-type and context-dependent, playing both protective and pathological roles in diseases. We have shown that FoxO4 represses smooth muscle cell (SMC) differentiation by interacting with and inhibiting the activity of myocardin, a fundamental transcriptional co-activator of smooth muscle genes (Liu et al., Dev Cell, 2005).

Moreover, FoxO4 also interacts with the transcription factor Sp1 and activates the transcription of the matrix metalloproteinase 9 (MMP9) in response to TNFα signaling in SMCs (Li et al., MCB, 2007). As a consequence of the ability of FoxO4 to modulate the phenotype of SMCs, inhibition of FoxO4 expression reduces the ability of SMCs to migrate in vitro and inhibits neointimal formation in vivo.

We found that FoxO4 can also play a protective role in human diseases through its ability to inhibit NF-κB-activated gene transcription. My lab was the first to discover that FoxO4 is an endogenous inhibitor of NF-κB and identified a novel function of FoxO4 in the regulation of NF-κB mediated mucosal immunity. FoxO4-deficiency is associated with elevated susceptibility to chemical-induced colitis (Zhou et al., Gastroenterology, 2009) and high-fat diet induced atherosclerosis (Zhu et al., Atherosclerosis, 2011). Our current focus is on the role of FoxO4 in the post-myocardial infarction ventricular remodeling.