Research Proposal; The best evidence that atherosclerosis is a proliferative lesion is the fact that plaques contain a large monoclonal population of cells. Although monoclonality can only arise through multiple generations of cell replication, there has been little progress in understanding how monoclonality arises or how cell growth is regulated at this critical time. Using a newly-developed PCR-based assay for X chromosome inactivation, I will first determine the cell type responsible for monoclonality in plaque. I will then study the X-inactivation patch architecture of normal vessels and a spectrum of evolving atherosclerotic plaques. This will determine whether the aorta is assembled in broad layered patches of X-inactivation before plaques form, or if monoclonal expansion instead occurs coincident with lesion formation. If monoclonal expansion is linked to plaque growth, this implies that the plaque smooth muscle cells are somehow unique compared to their polyclonal precursors. To determine if vascular injury, in general, selects a """"""""proliferogenic"""""""" clone of smooth muscle cells, I will determine if multiple forms of hyperplastic vascular disease are monoclonal. Next, having identified the time course of monoclonal expansion, I will determine if increased expression of growth factors can account for this cell proliferation. Finally, I will begin to test the hypothesis that somatic mutations underlie atherosclerosis, by determining if plaques have evidence of genomic instability or mutations in tumor suppressor genes.

Agency
National Institute of Health (NIH)
Institute
National Heart, Lung, and Blood Institute (NHLBI)
Type
Clinical Investigator Award (CIA) (K08)
Project #
5K08HL003094-02
Application #
2519170
Study Section
Research Training Review Committee (RTR)
Project Start
1996-09-01
Project End
2000-08-31
Budget Start
1997-09-01
Budget End
1998-08-31
Support Year
2
Fiscal Year
1997
Total Cost
Indirect Cost
Name
University of Washington
Department
Pathology
Type
Schools of Medicine
DUNS #
135646524
City
Seattle
State
WA
Country
United States
Zip Code
98195
Murry, Charles E; Whitney, Marsha L; Reinecke, Hans (2002) Muscle cell grafting for the treatment and prevention of heart failure. J Card Fail 8:S532-41
Reinecke, Hans; Poppa, Veronica; Murry, Charles E (2002) Skeletal muscle stem cells do not transdifferentiate into cardiomyocytes after cardiac grafting. J Mol Cell Cardiol 34:241-9
Whitney, M L; Otto, K G; Blau, C A et al. (2001) Control of myoblast proliferation with a synthetic ligand. J Biol Chem 276:41191-6
Zhang, M; Methot, D; Poppa, V et al. (2001) Cardiomyocyte grafting for cardiac repair: graft cell death and anti-death strategies. J Mol Cell Cardiol 33:907-21
Murry, C E; Jerome, K R; Reichenbach, D D (2001) Fatal parvovirus myocarditis in a 5-year-old girl. Hum Pathol 32:342-5
Reinecke, H; MacDonald, G H; Hauschka, S D et al. (2000) Electromechanical coupling between skeletal and cardiac muscle. Implications for infarct repair. J Cell Biol 149:731-40
Reinecke, H; Murry, C E (2000) Transmural replacement of myocardium after skeletal myoblast grafting into the heart. Too much of a good thing? Cardiovasc Pathol 9:337-44
Reinecke, H; Zhang, M; Bartosek, T et al. (1999) Survival, integration, and differentiation of cardiomyocyte grafts: a study in normal and injured rat hearts. Circulation 100:193-202
Chung, I M; Schwartz, S M; Murry, C E (1998) Clonal architecture of normal and atherosclerotic aorta: implications for atherogenesis and vascular development. Am J Pathol 152:913-23
Murry, C E; Gipaya, C T; Bartosek, T et al. (1997) Monoclonality of smooth muscle cells in human atherosclerosis. Am J Pathol 151:697-705