Associate Provost for Research Boston University Medical Campus
NIA - National Institute on Aging	Research Resources

Abstract

Abstract: DESCRIPTION: 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.

Thesaurus Terms:
cell cycle, cell growth regulation, cyclin dependent kinase, hypertrophy, molecular pathology, phosphotransferase, protein structure function, vascular smooth muscle
aorta disorder, cell differentiation, cell proliferation, gene expression, genetic promoter element, genetic regulation, hypertension, mitotic spindle, phosphorylation, polyploidy, protein protein interaction
bromodeoxyuridine, flow cytometry, genetically modified animal, laboratory mouse, nuclear runoff assay, site directed mutagenesis, tissue /cell culture

Institution:	BOSTON UNIVERSITY MEDICAL CAMPUS
	715 ALBANY ST, 560
	BOSTON, MA 021182394
Fiscal Year:	2005
Department:	MEDICINE
Project Start:	15-MAR-2001
Project End:	28-FEB-2006
ICD:	NATIONAL INSTITUTE ON AGING
IRG:	PTHA