RAS DEPENDENT SIGNALING IN CARDIAC HYPERTROPHY

Project Details

Description

DESCRIPTION (adapted from the applicant's abstract): Cardiac hypertrophy in
response to load or agonists characteristically entails the induction of a
so-called "fetal" program of cardiac gene expression, superimposed on a
generalized increase in cellular RNA and protein content. The signaling
pathways involved in cardiac hypertrophy have been extensively studied,
mostly in relation to the transcriptional induction of the fetal genes.
However, upregulation of the fetal genes and total cellular protein are
independent events. Hence, the signaling pathways mediating the latter
effect remain largely unknown. Preliminary data suggest that the GTP
binding protein Ras and its down stream effector Ras-GAP are involved in the
upregulation of global gene expression. This was accompanied, and may be
explained, by enhanced RNA polymerase 11 phosphorylation, and expression of
its major kinase, cyclin dependent kinase 7 (cdk 7), in the cardiac
myocytes. The aims in this proposal are: 1) To identify the functional
domain(s) of Ras-GAP involved in mediating its effect on gene expression,
and to use the yeast two hybrid system to identify its target proteins. 2)
To test the functional importance of cdk7 for Ras and GAP-dependent
signaling by engineering a dominant negative cdk 7. 3) To test the effect
of Ras-GAP in vivo in a transgenic animal model over-expressing the protein
in the heart. As a direct evaluation of the role of Ras in the development
and maintenance of cardiac hypertrophy, the principal investigator will test
the effect of the farnesyltransferase Ras inhibitor L-739,749 on the
development and regression of cardiac hypertrophy in experimental rat
models.
StatusFinished
Effective start/end date1/5/9812/31/03

Funding

  • National Heart, Lung, and Blood Institute: $119,115.00
  • National Heart, Lung, and Blood Institute: $55,000.00
  • National Heart, Lung, and Blood Institute
  • National Heart, Lung, and Blood Institute: $53,320.00
  • National Heart, Lung, and Blood Institute
  • National Heart, Lung, and Blood Institute: $69,323.00

ASJC

  • Cardiology and Cardiovascular Medicine

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