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 completed studies demonstrating that p27Kip1 plays a major role in cardiovascular disease through its effects on the proliferation of bone marrow (BM)-derived immune cells that migrate into vascular lesions. Lesion formation after mechanical arterial injury is markedly increased in mice with homozygous deletion of p27Kip1 and is characterized by prominent vascular infiltration by immune and inflammatory cells. Vascular occlusion is substantially increased when BM-derived cells from p27-/- mice repopulate vascular lesions induced by mechanical injury in p27+/+ recipients, in contrast to p27+/+ BM donors. In addition, RAG+/+ BM markedly exacerbated vascular proliferative lesions compared to RAG-/-donors, suggesting a strong contribution of immune cells to vascular injury. Taken together, these findings suggest that vascular repair and regeneration is regulated by the proliferation of BM-derived hematopoietic and non-hematopoietic cells through a p27Kip1-dependent mechanism and that immune cells largely mediate these effects. A second area of research is a structure and function analysis of a serine-threonine kinase, KIS, which phosphorylates p27 at serine 10, leading to nuclear export and degradation of p27. Our laboratory has previously cloned and characterized this kinase, and studies examining the structure and function of KIS, including transcriptional control of the KIS promoter, the phenotype of KIS knock-out in mice, and knock-in mutations of the different phosphorylation sites of p27 in mice are in progress in order to better understand the molecular regulation of p27 by KIS and other known kinases. A clinical study of in-stent restenosis, called CardioGene, is in progress in order to understand the genetic susceptibility of this complex, common cardiovascular disease. Patients undergoing primary stenting have been prospectively enrolled at three clinical sites. Patients have been followed for one year, and the genetic profiles of patients with in-stent restenosis are being 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.
Showing the most recent 10 out of 39 publications
