Our laboratory is interested in the molecular genetics of vascular diseases. We utilize several approaches, including molecular and cellular biology studies, genetic studies in mice, and clinical investigations in patients with vascular diseases. One area of research focuses on the molecular biology of the cyclin-dependent kinase inhibitor, p27. Previous studies from our lab identified p27 as a major regulator of vascular cell proliferation during arterial remodeling. We have cloned and characterized a serine-threonine kinase, KIS, which phosphorylates p27 at serine 10, leading to nuclear export and degradation of p27. This nuclear kinase is growth factor dependent, and overexpression of KIS leads to cell cycle progression and cell proliferation. Ongoing studies in the laboratory are investigating the structure and function of KIS, including transcriptional control of the KIS promoter. We are also examining the phenotype of KIS knock-out mice, as well as knock-in mutations of the different phosphorylation sites of p27 in mice, in order to better understand the molecular regulation of p27 by KIS and other known kinases. Additional studies focus on developmental regulation of KIS and p27 in the heart and vasculature. A second area of research is phenotypic analysis of the vascular responses of p27 and p21 null mice to vascular stresses. Mice lacking p27 have accelerated lesion formation following vascular injury, due to uncheck proliferation of vascular smooth muscle cells, T-cell inflammatory responses, and altered collagen formation. Crosses with p21 and RAG null mice are examining the mechanisms of apoptosis, inflammation and proliferation. Interestingly, a deficiency of p27 in an apoE null background severely accelerates atherosclerosis. We have undertaken a clinical study of in-stent restenosis, called Cardiogene, in order to understand the genetic susceptibility of this complex, common cardiovascular disease. Patients undergoing primary stenting are being prospectively enrolled at three clinical sites. Patients are followed for one year, and the genetic profiles of patients with in-stent restenosis are compared to patients with no restenosis. Genetic analyses include gene expression profiling, serum proteomics, and genotyping using candidate gene and genome-wide scanning approaches. The goal is to identify gene, RNA and protein profiles of patients with recurrent in-stent restenosis in order to better diagnose and triage patients undergoing these procedures and to potentially refine therapeutics. Taken together, these studies focus on the molecular genetics of vascular diseases, with an emphasis on cell cycle regulation of proliferation, inflammation and apoptosis. Understanding the molecular pathophysiology of vascular diseases, such as in-stent restenosis, is critical to the design and development of novel therapeutics.
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