Recent studies have suggested a link between some cases of restenosis and the herpesvirus, human cytomegalovirus (HCMV). A closer examination revealed that this relationship correlated with HCMV immediate early (IE) gene expression in restenosis lesions and the stabilization and inactivation of the p53 tumor suppressor. These observations suggest a hypothesis that restenosis is caused by p53 inactivation by HCMV infection or other events that down regulate p53 activity. We propose to further examine the relationships between the HCMV IE gene products, p53, and cell proliferation control. We will examine whether HCMV IE gene expression contributes to the overproliferation of smooth muscle cells observed in restenosis. We will address these issues by employing a powerful approach, which utilizes replication, defective, recombinant adenoviruses to transiently introduce and express genes of interest. By using this approach, we propose: (1) to determine the extent to which HCMV IE gene expression affects cell cycle regulation; (2) to determine the biochemical mechanisms by which HCMV IE gene expression affects cell cycle - alteration of RB and p53 functions; and (3) to examine the effects of HCMV IE gene expression on early passage arterial smooth muscle cells. Together, these experiments will clarify the role of HCMV infection in restenosis.

Agency
National Institute of Health (NIH)
Institute
National Heart, Lung, and Blood Institute (NHLBI)
Type
Predoctoral Individual National Research Service Award (F31)
Project #
1F31HL010334-01
Application #
6081167
Study Section
Special Emphasis Panel (ZRG1-ALTX-4 (03))
Program Officer
Springfield, Sanya A
Project Start
2000-07-25
Project End
Budget Start
2000-02-01
Budget End
2001-01-31
Support Year
1
Fiscal Year
2000
Total Cost
$17,560
Indirect Cost
Name
University of Massachusetts Medical School Worcester
Department
Genetics
Type
Schools of Medicine
DUNS #
660735098
City
Worcester
State
MA
Country
United States
Zip Code
01655
Castillo, Jonathan P; Frame, Fiona M; Rogoff, Harry A et al. (2005) Human cytomegalovirus IE1-72 activates ataxia telangiectasia mutated kinase and a p53/p21-mediated growth arrest response. J Virol 79:11467-75
Castillo, Jonathan P; Kowalik, Timothy F (2002) Human cytomegalovirus immediate early proteins and cell growth control. Gene 290:19-34
Castillo, J P; Yurochko, A D; Kowalik, T F (2000) Role of human cytomegalovirus immediate-early proteins in cell growth control. J Virol 74:8028-37