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. Our focus is on the genetics and genomics of vascular remodeling during common, complex cardiovascular diseases and during premature aging syndromes.? ? Through our investigations of the signaling pathways mediated by the cyclin kinase inhibitor, p27, we identified (using a yeast two-hybrid approach) the protein arginine N-methyltransferase, PRMT2. Arginine methylation by PRMT2 is a posttranslational modification important in the regulation of protein signaling, and we have determined PRMT2 effects on diverse cellular functions, including the retinoblastoma gene product (RB), NF-eB and leptin signaling. PRMT2 directly binds and regulates RB through its AdoMet binding domain, and PRMT2 represses E2F transcriptional activity in an RB-dependent manner. Interestingly, PRMT2 inhibits cell activation and promotes cell death through an NF-eB mechanism; that is, PRMT2 blocks nuclear export of IeB-a through a leptomycin-sensitive pathway, increasing nuclear IeB-a and decreasing NF-eB DNA binding. In work in progress, we have determined that PRMT2 is an endogenous regulator of leptin sensitivity through arginine methylation of STAT3.? ? We are continuing data analysis of a clinical study of in-stent restenosis (ISR) in order to understand the genetic susceptibility of this complex, common cardiovascular disease. To investigate the genetic basis of ISR, we have conducted a case control genome wide association study of ~116,000 SNPs assayed in 407 patients. We undertook a regional haplotype analysis and tested for association with ISR, using a global Bonferroni correction. We have identified eight candidate susceptibility loci for ISR, five of which contain genes which express proteins that are observed in normal, atherosclerotic and restenotic human coronary arteries. Replication studies are in progress. Our goal is to identify genomic profiles of patients with ISR in order to better diagnose and triage patients undergoing these procedures and to potentially refine therapeutics.? ? Finally, we have collaborated with the Francis Collins lab on investigations of the premature aging syndrome, Hutchinson-Gilford Progeria Syndrome. Work has focused on the role of farnesyltransferase inhibitors (FTIs) to prevent the characteristic nuclear abnormalities in HGPS by inhibiting farnesylation of progerin protein. Ongoing studies of FTI treatment of transgenic mice overexpressing progerin will address the potential of FTIs to prevent and possibly reverse the abnormal vascular remodeling which leads to premature myocardial infarction and stroke.? ? In summary, our studies of the molecular genetics of vascular remodeling have explored PRMT2 signaling pathways, the genomics of ISR, and pathological arterial remodeling in HGPS.
| Blaisdell, Carol J; Gail, Dorothy B; Nabel, Elizabeth G (2009) National Heart, Lung, and Blood Institute perspective: lung progenitor and stem cells--gaps in knowledge and future opportunities. Stem Cells 27:2263-70 |
| Crook, Martin F; Olive, Michelle; Xue, Hai-Hui et al. (2008) GA-binding protein regulates KIS gene expression, cell migration, and cell cycle progression. FASEB J 22:225-35 |
| Nabel, Elizabeth G (2008) The physician-scientist: a value proposition. J Clin Invest 118:1233-5 |
| Merideth, Melissa A; Gordon, Leslie B; Clauss, Sarah et al. (2008) Phenotype and course of Hutchinson-Gilford progeria syndrome. N Engl J Med 358:592-604 |
| Capell, Brian C; Collins, Francis S; Nabel, Elizabeth G (2007) Mechanisms of cardiovascular disease in accelerated aging syndromes. Circ Res 101:13-26 |
| Kiley, James P; Nabel, Elizabeth G (2007) Treating COPD. N Engl J Med 356:867 |
| Daar, Abdallah S; Singer, Peter A; Persad, Deepa Leah et al. (2007) Grand challenges in chronic non-communicable diseases. Nature 450:494-6 |
| Nabel, Elizabeth G; Shurin, Susan B; Simons-Morton, Denise G et al. (2007) Data and safety monitoring of rosiglitazone trials. Lancet 369:2077 |
| GAIN Collaborative Research Group; Manolio, Teri A; Rodriguez, Laura Lyman et al. (2007) New models of collaboration in genome-wide association studies: the Genetic Association Information Network. Nat Genet 39:1045-51 |
| Nabel, Elizabeth G (2006) The Women's Health Initiative. Science 313:1703 |
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