GENETIC MECHANISMS OF ESTROGEN ATHEROPROTECTION

Project: Research project

Project Details

Description

The candidate is a Hispanic female (U.S. citizen) from Santiago,
Chile. I am clinically trained in cardiovascular medicine and
have interest and expertise in heart disease in women. As a
newly promoted Associate Professor at the University of
California, Davis I have prior research experience in cellular
and molecular biology investigating the actions of vasoactive
peptides in endothelial cell growth and function in vitro. My
clinical interest in estrogen as a modulator of cardiovascular
risk and mortality in women, leads me to now seek to extend my
prior research work in a new research direction to investigate
mechanisms of hormonal regulation of vascular gene expression in
atheroprotection. I am at a critical juncture in my career where
clinical responsibilities threaten my future research progress. I need and seek protected research time and additional research
training under the guidance of a mentor in three areas: [1] the
use of murine models of disease, [2] molecular genetics, and [3]
physiologic studies to investigate functional significance of
genetic changes. To attain this goal I have enlisted the help of
Dr. Stephen Barthold as mentor and Dr. Beverly Paigen as co-
mentor. Dr. Barthold is an expert in mouse biology and directs
the UCDavis Center for Comparative Medicine which oversees the
Mouse Biology Program. Dr. Paigen has expertise in murine models
of atherosclerosis and is a senior research scientist at the
Jackson Laboratories. Together, we propose a research
development plan with five components: [1] didactic course work
at UCDavis, [2] didactic and hand-on laboratory work at the
Jackson Laboratory, [3] participation in research seminars and
lectures, [4] attendance at National and International scientific
meetings, and p5[ a state-of-the-art hands-on research program.
The research development plan provides seamless integration with
the research plan. The overall goal of the research proposal is to understand the
action of estradiol, the estrogen receptor, and estrogen/receptor
interactions on atheroprotection, vascular function and gene
expression in mice. Previous studies suggest the possibility of
both receptor-dependent and independent mechanisms of
atheroprotection by estrogen, yet surprisingly, genetic
mechanisms of atheroprotection by estrogen have not been
investigated and a suitable atherogenic mouse model has not been
developed. In conjunction with physiological studies we wish to
use established mouse genetic models, and create new genetically
engineered models, in order to investigate the overall hypothesis
that: [1] The atheroprotective action of estrogen is mediated by
the estrogen receptor, and [2] The beneficial effects of estrogen
are accompanied by expression of estrogen-sensitive genes that
regulate atheroprotection in the vascular wall. To investigate
this hypothesis we will pursue the following specific aims: [1]
Develop an estrogen receptor alpha deficient and sufficient mouse
model of atherosclerosis and characterize it by quantitative
histology of atheroma and vasomotor tone using aortic tension
assays in vitro. [2] Use the model developed in aim 1 to
identify vascular genes that are up-regulated by estrogen by
differential gene expression RNA fingerprinting by RT-PCR, and
examine the role of selected other candidate genes that are
likely to be influenced by estrogen (Ath 1, CASH, PAI-1, and
aldose reductase) by Northern analysis. [3] Use molecular
genetic methods for targeted deletion of mouse genes to determine
the physiologic role of specific genes in newly created gene
knock out mice, using the parameters optimized in Aim 1. The research and training environment available to the candidate
for the conduct of these studies of vascular function and
genetics is robust, the candidate's commitment is very strong,
and the potential for success substantial. Advances in our basic
understanding of mechanisms of hormone action could lead to more
effective strategies for treatment of coronary artery disease in
both men and women.
StatusFinished
Effective start/end date6/1/9911/30/04

Funding

  • National Institutes of Health: $136,687.00
  • National Institutes of Health
  • National Institutes of Health: $136,687.00
  • National Institutes of Health: $136,750.00
  • National Institutes of Health: $136,687.00

ASJC

  • Medicine(all)

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