![](https://webarchive.library.unt.edu/web/20090509010725im_/https://www.genome.gov/Images/spacer2.gif) |
![](https://webarchive.library.unt.edu/web/20090509010725im_/https://www.genome.gov/Images/spacer2.gif) |
Division of Intramural Research
![](https://webarchive.library.unt.edu/web/20090509010725im_/https://www.genome.gov/Images/spacer2.gif) |
Overview |
![](https://webarchive.library.unt.edu/web/20090509010725im_/https://www.genome.gov/Images/spacer2.gif) |
Vision, Mission and Values |
![](https://webarchive.library.unt.edu/web/20090509010725im_/https://www.genome.gov/Images/spacer2.gif) |
Organizational Chart |
![](https://webarchive.library.unt.edu/web/20090509010725im_/https://www.genome.gov/Images/spacer2.gif) |
Research Branches
|
![](https://webarchive.library.unt.edu/web/20090509010725im_/https://www.genome.gov/Images/spacer2.gif) |
Research Investigators Profiles, publications, links |
![](https://webarchive.library.unt.edu/web/20090509010725im_/https://www.genome.gov/Images/spacer2.gif) |
Clinical Research
Clinical trials, patient recruitment, IRB, FAQ, Overview |
![](https://webarchive.library.unt.edu/web/20090509010725im_/https://www.genome.gov/Images/spacer2.gif) |
NHGRI Affiliated Centers CIDR, CRGGH, NCGC, NISC
|
![](https://webarchive.library.unt.edu/web/20090509010725im_/https://www.genome.gov/Images/spacer2.gif) |
Online Research Resources Developed at NHGRI
Databases, software, tools, more. |
![](https://webarchive.library.unt.edu/web/20090509010725im_/https://www.genome.gov/Images/spacer2.gif) |
Division of Intramural Research Calendar
Workshops, conferences, seminar series, courses, more. |
![](https://webarchive.library.unt.edu/web/20090509010725im_/https://www.genome.gov/Images/spacer2.gif) |
Books and Publications |
|
![](https://webarchive.library.unt.edu/web/20090509010725im_/https://www.genome.gov/Images/spacer2.gif) |
![](https://webarchive.library.unt.edu/web/20090509010725im_/https://www.genome.gov/Images/spacer2.gif) |
In Other Sections:
|
![](https://webarchive.library.unt.edu/web/20090509010725im_/https://www.genome.gov/Images/spacer2.gif) |
![](https://webarchive.library.unt.edu/web/20090509010725im_/https://www.genome.gov/Images/leftnav/navbottom_research.gif) |
|
![](https://webarchive.library.unt.edu/web/20090509010725im_/https://www.genome.gov/Images/leftnav/navright2_research.gif) |
![](https://webarchive.library.unt.edu/web/20090509010725im_/https://www.genome.gov/Images/spacer2.gif)
Dr. Nabel's laboratory seeks to identify the molecular, cellular, and genetic mechanisms that cause vascular disorders. In particular, her research focuses on defining the pathways that regulate cell growth in the vasculature, remodel the vasculature after injury, and lead to genetic susceptibility to vascular diseases. Taken together, these studies focus on the molecular genetics of vascular diseases, with an emphasis on cell cycle regulation of proliferation, inflammation, and apoptosis.
Cardiovascular diseases are the leading cause of morbidity and mortality in industrialized countries. Most cardiovascular diseases result from complications of atherosclerosis, which is a chronic and progressive inflammatory condition characterized by excessive cellular proliferation of vascular smooth muscle cells, endothelial cells, and inflammatory cells that leads to occlusive vascular disease, myocardial infarction, and stroke. Recent studies have revealed the important role of cyclins, cyclin-dependent kinases (CDKs), and cyclin-dependent kinase inhibitors (CKIs) in vascular and cardiac tissue injury, inflammation, and wound repair. Dr. Nabel's research seeks to understand the circuitry of the cyclin-CDK-CKI interactions in normal physiology and disease pathology, providing a better understanding of the molecular mechanisms of cardiovascular diseases. This approach will hopefully lead to the rational design of new classes of therapeutic agents.
Given role of cyclins in vascular health, one major focus of Dr. Nabel's laboratory is the study of CKIs, which are primarily involved in inhibiting the proliferation of a variety of normal cell types. Dr. Nabel's laboratory previously identified a particular CKI, known as p27Kip1, as a major regulator of vascular cell proliferation during arterial remodeling. In one set of studies, her group found that p27Kip1 plays a major role in cardiovascular disease through its effects on the proliferation of bone marrow-derived immune cells that migrate into vascular lesions. To demonstrate whether p27Kip1 regulates arterial wound repair, Dr. Nabel and her coworkers recently subjected p27-/- (homozygous knockout), p27+/- (heterozygous knockout), and p27+/+ (wild-type) mice to a wire injury in the femoral artery and examined subsequent cell proliferation and lesion formation. Cell proliferation was significantly increased in the innermost lining of the blood vessels of p27-/- mouse arteries compared with p27+/+ arteries. Arterial lesions also were markedly increased in the p27-/- mice compared with those of p27+/+ mice. The heterozygous knockout mice (p27-/+) had an intermediate phenotype. These findings suggest that vascular repair and regeneration are regulated by the proliferation of hematopoietically and nonhematopoietically derived cells through a p27Kip1-dependent mechanism, with immune cells largely mediating these effects.
A related area of Dr. Nabel's program focuses on the structural and functional analysis of a serine-threonine kinase called kinase interacting stathmin, or KIS. A nuclear protein that binds the C-terminal domain of p27Kip1, KIS phosphorylates a serine residue at position 10 (Ser 10) in the sequence and thereby promotes its export to the cytoplasm. KIS is activated by mitogens during G0/G1, and expression of KIS overcomes growth arrest induced by p27Kip1. Depletion of KIS with small interfering RNA (siRNA) inhibits Ser 10 phosphorylation and enhances growth arrest. In addition, treating p27-/- cells with KIS siRNA causes them to grow and progress to S/G2, similar to control-treated cells, implicating p27Kip1 as the critical target for KIS. Dr. Nabel's laboratory previously cloned and characterized the gene encoding this kinase and is now conducting studies to examine its structure and function, including the transcriptional control of the KIS promoter, the phenotypic consequences of knockout out the KIS gene in mice, and the effect of knock-in mutations at different phosphorylation sites of p27.
Dr. Nabel's group also is involved in a clinical study of the genetics of restenosis, which is the recurrence of a blockage in an artery after it has been manually reopened with an artificial stent. Restenosis is a major limitation of stent therapy for coronary artery disease. In this study, the investigators are following patients who have received bare metal stents for the treatment of a blocked coronary artery and then comparing the genetic profiles of patients with restenosis with those of patients with no restenosis. The 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 restenosis, so as to advance our understanding of the pathogenesis of this problem and to target potential therapies.
Last Reviewed: April 28, 2009
|
![](https://webarchive.library.unt.edu/web/20090509010725im_/https://www.genome.gov/Images/spacer2.gif) |
![](https://webarchive.library.unt.edu/web/20090509010725im_/https://www.genome.gov/Images/spacer2.gif)
![](https://webarchive.library.unt.edu/web/20090509010725im_/https://www.genome.gov/Images/spacer2.gif) |
![](https://webarchive.library.unt.edu/web/20090509010725im_/https://www.genome.gov/Images/spacer2.gif)
Other Genome Technology Branch Investigators
![](https://webarchive.library.unt.edu/web/20090509010725im_/https://www.genome.gov/Images/spacer2.gif)
|
![](https://webarchive.library.unt.edu/web/20090509010725im_/https://www.genome.gov/Images/spacer2.gif) |
![](https://webarchive.library.unt.edu/web/20090509010725im_/https://www.genome.gov/Images/rightnav/separator_image2.gif) |
![](https://webarchive.library.unt.edu/web/20090509010725im_/https://www.genome.gov/Images/spacer2.gif) |
Christopher P. Austin, M.D.
Andy Baxevanis, Ph.D.
Robert W. Blakesley, Ph.D.
Gerard Bouffard, Ph.D.
Lawrence C. Brody, Ph.D.
Shawn Burgess, Ph.D.
Settara C. Chandrasekharappa, Ph.D.
Laura L. Elnitski, Ph.D.
Eric D. Green, M.D., Ph.D.
James Inglese, Ph.D.
Elliott Margulies, Ph.D.
James C. Mullikin, Ph.D.
Tyra Wolfsberg, Ph.D.
|
![](https://webarchive.library.unt.edu/web/20090509010725im_/https://www.genome.gov/Images/spacer2.gif) |
|
|
|
![](https://webarchive.library.unt.edu/web/20090509010725im_/https://www.genome.gov/Images/spacer2.gif) |