Jeffrey D. Alexis, M.D.

Research in Dr. Alexis' lab focuses on signaling pathways that regulate intimal proliferation. Intimal proliferation occurs in several pathologic states including transplant arteriopathy and restenosis following angioplasty. Smooth muscle cell inflammation and proliferation are important aspects of this pathology. Our research focuses on the role of breakpoint cluster region (Bcr) in the development of intimal proliferation. Bcr was first identified for its role as part of the Philadelphia chromosome in chronic myelogenous leukemia. Bcr is also a serine/threonine kinase. We have demonstrated that Bcr plays a role in vascular wall intimal proliferation. We have shown that Bcr regulates both inflammation and proliferation in vascular smooth muscle cells (VSMC). Specifically, we have shown that dominant negative Bcr reversed Angiotensin II-mediated inhibition of the transcription factor PPAR gamma. We have found that Angiotensin II increases Bcr expression and kinase activation. We have shown that Bcr is present in the nucleus of smooth muscle cells and phosphorylates PPAR gamma. We have also shown that Bcr inhibits PPAR gamma transcriptional activation. This inhibition is via phosphorylation of PPAR gamma at S82, the site at which ERK 1/2 phosphorylates PPAR gamma (also leading to inhibition of PPAR gamma). Our data also demonstrate that Bcr enhances NF-kB transcriptional activity at least in part via inhibition of PPAR gamma. Intimal proliferation in low-flow carotid arteries was reduced in Bcr knockout mice compared with controls, demonstrating a critical role of Bcr on VSMC proliferation in vivo. Our current work focuses on Bcr signaling independent of PPAR gamma. We have identified the splicing factor UAP56 as another Bcr kinase substrate and we are now investigating the role of UAP56 in cellular proliferation.