The goal of this proposal is foster the development in five years of a productive scientist performing independent research on signal transduction and gene expression in vascular tissue. It will focus on studying how voltage-gated Ca2+ channels regulate gene expression in vascular smooth muscle cells (VSMCs). This will address clinically important issues such as vascular remodeling, which occurs in response to stimuli like chronic hypertension or endothelial injury, and results in VSMC hypertrophy and hyperplasia. Previous work has shown that Ca2+ entry at the cell surface can regulate VSMC growth and proliferation. It has recently been demonstrated that, in hippocampal neurons, activation of L-type Ca2+ channels can lead to phosphorylation of the nuclear transcription factor CREB, suggesting a pathway by which Ca2+ entry can lead to nuclear events. The preliminary studies demonstrate that Ca2+ entry in VSMCs can also lead to CREB phosphorylation. In this application, the following three specific aims will be addressed: 1. The location and mode of Ca2+ entry that leads to gene expression in VSMCs will be determined. 2. The downstream transcriptional events triggered by Ca2+ entry in VSMCs will be explored. 3. The intermediates along the pathway by which Ca2+ entry leads to gene expression in VSMCs will be defined. These questions will be approached with a powerful combination of techniques, including patch clamp electrophysiology of single smooth muscle cells, immunocytochemistry, molecular biology and real time-imaging of Ca2+ and calmodulin distributions.

Agency
National Institute of Health (NIH)
Institute
National Heart, Lung, and Blood Institute (NHLBI)
Type
Clinical Investigator Award (CIA) (K08)
Project #
5K08HL003743-02
Application #
6043685
Study Section
Special Emphasis Panel (ZHL1-CSR-Y (M2))
Project Start
1998-08-01
Project End
2003-07-31
Budget Start
1999-08-01
Budget End
2000-07-31
Support Year
2
Fiscal Year
1999
Total Cost
Indirect Cost
Name
Stanford University
Department
Biophysics
Type
Schools of Medicine
DUNS #
800771545
City
Stanford
State
CA
Country
United States
Zip Code
94305