Endothelial cell (EC) phenotypes display remarkable heterogeneity in health and disease. An important goal in vascular biology is to understand the molecular mechanisms underlying the spatial and temporal modulation of EC phenotypes. This competing renewal application is an extension of our previous work aimed towards elucidating the role of forkhead (FOXO) transcription factors in EC biology. Three novel and exciting aspects of FOXO biology have emerged in the past 3 years, which together with our own published data and preliminary results provide a strong foundation for the current proposal: 1) despite the fact that FOXO proteins are ubiquitously expressed, FOXO- deficient mice display a vascular phenotype, whether the gene is deleted during embryogenesis or in adults, 2) the vascular phenotype is organ-specific and FOXO-deficient ECs from different organs demonstrate different gene expression patterns and functional changes, and 3) FOXO proteins (at least in other cell types) have been shown to bind to and/or interact with a broad spectrum of transcription factors. Based on these considerations, we hypothesize that FOXO proteins (in particular FOXO1) cooperate with other transcription factors to regulate EC phenotypes. The overall goal is to identify FOXO1-associated transcriptional networks in ECs, to understand how these mediate vascular bed-specific gene expression, and to define the in vivo role of FOXO1 in the intact endothelium.
Aim 1 is to characterize functional interactions between FOXO1 and other transcription factors in ECs.
Aim 2 is to characterize combinatorial gene regulation by FOXO1 and NF-kB in ECs.
Aim 3 is to analyze the effect of conditional FOXO1 over-expression and knockout on EC function and dysfunction in normal and pathological states.

Public Health Relevance

The proposal is significant in that it will provide important insights into the mechanisms (hence therapeutic potential) of FOXO1-mediated EC signal transduction.

Agency
National Institute of Health (NIH)
Institute
National Heart, Lung, and Blood Institute (NHLBI)
Type
Research Project (R01)
Project #
5R01HL077348-08
Application #
8449758
Study Section
Vascular Cell and Molecular Biology Study Section (VCMB)
Program Officer
Gao, Yunling
Project Start
2004-07-01
Project End
2014-03-31
Budget Start
2013-04-01
Budget End
2014-03-31
Support Year
8
Fiscal Year
2013
Total Cost
$422,280
Indirect Cost
$179,295
Name
Beth Israel Deaconess Medical Center
Department
Type
DUNS #
071723621
City
Boston
State
MA
Country
United States
Zip Code
02215
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