The objective of this proposal is to determine the role that Akt1 plays in the phenomenon of vascular smooth muscle cell (VSMC) polyploidization. It is well known that pathological remodeling of vascular smooth muscle in capacitance arteries is responsible for arterial stiffness and contributes to the development of associated coronary and ventricular pathologies. Previous studies have shown that the hypertrophy of vascular smooth muscle cells (VSMCs) is the main factor responsible for the enlargement and rigidity of the aorta and that hypertrophied. VSMCs on capacitance arteries of hypertensive individuals and animals are frequently polyploid. Our laboratory has found that the aortic vascular smooth muscles of hypertensive animals have elevated levels and activity of PKB/Akt1, an enzyme that provides signals for cell growth and survival. We have also seen that ectopic expression of Akt1 induces VSMC polyploidization and up regulation of Cks1, a Cyclin B/Cdc2-associated protein that promotes the progression of mitosis. We hypothesize that Cks1 mediates some of the effects of Akt1 on VSMC mitosis. To test these hypotheses, we propose the following aims:
Aim 1 : To determine the effect of Akt1 gene transfer on the activity of the mitotic spindle and postmitotic cell cycle checkpoints in VSMCs.
Aim 2 : To determine the molecular bases for the up regulation of Cks 1 expression in VSMCs with activated Akt 1.
Aim 3 : To determine the requirement of Cks1 function for Akt1-induced VSMC polyploidization.
Aim 4 : To generate transgenic animals that over express Cks1 or Akt1 in vascular smooth muscle.

Agency
National Institute of Health (NIH)
Institute
National Institute on Aging (NIA)
Type
Research Project (R01)
Project #
5R01AG017241-04
Application #
6717674
Study Section
Pathology A Study Section (PTHA)
Program Officer
Kohanski, Ronald A
Project Start
2001-03-15
Project End
2006-02-28
Budget Start
2004-04-15
Budget End
2005-02-28
Support Year
4
Fiscal Year
2004
Total Cost
$244,500
Indirect Cost
Name
Boston University
Department
Internal Medicine/Medicine
Type
Schools of Medicine
DUNS #
604483045
City
Boston
State
MA
Country
United States
Zip Code
02118
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