Endothelial cell differentiation and establishment of blood vessel identity is essential for vascular function in both normal and disease settings. For example, in the developing embryo differentiation of arterial and venous endothelial cells is essential for proper vessel patterning and circulatory function. Similarly, perturbation of blood vessel identity in a number of congenital diseases can lead to vascular anomalies, such as arteriovenous malformations. Thus, understanding the molecular basis of normal endothelial differentiation would give us insights onto pathological blood vessel formation and facilitate the engineering of distinct blood vessel types. While transcriptional hierarchies controlling cellular differentiation have been extensively characterized in other tissues, much less is known about such programs in endothelial cells. The studies proposed in this application will begin to address the control of artery and vein differentiation at the transcriptional level in endothelial cells. In particular, we will identify cis regulatory elements in the human genome that are responsible for arterial and venous endothelial-specific gene expression. This will be accomplished through the genome-wide identification of binding sites for general transcriptional regulatory proteins known to reliably mark enhancer and repressor elements. Subsequent computational analyses will allow us to identify common cis regulatory sequences that correlate with artery or vein specific gene expression. These will shed possible insight onto upstream transcriptional regulators. To functionally validate the activity of putative artery and vein cis elements, we will perform in vivo reporter assays on human elements using the zebrafish as a model system. The transparency and external development of the zebrafish embryo, coupled with its rapid development will allow us to comprehensively determine the activity of a large number of cis elements for numerous artery and vein restricted genes. Together, these studies will allow us to map the transcriptional regulatory inputs that contribute to arterial and venous endothelial differentiation and blood vessel identity.

Public Health Relevance

Blood vessels have different functions and appearances (e.g. arteryversus vein) depending on their anatomical location. These differences are apparent in early embryos and may play a role in disease settings. However, little is known about how these differences arise. In this proposal, we will focus on uncovering the signals that govern artery and vein identity.

Agency
National Institute of Health (NIH)
Institute
National Heart, Lung, and Blood Institute (NHLBI)
Type
Exploratory/Developmental Grants (R21)
Project #
5R21HL106212-02
Application #
8204567
Study Section
Cardiovascular Differentiation and Development Study Section (CDD)
Program Officer
Schramm, Charlene A
Project Start
2010-12-03
Project End
2012-11-30
Budget Start
2011-12-01
Budget End
2012-11-30
Support Year
2
Fiscal Year
2012
Total Cost
$205,625
Indirect Cost
$80,625
Name
University of Massachusetts Medical School Worcester
Department
Genetics
Type
Schools of Medicine
DUNS #
603847393
City
Worcester
State
MA
Country
United States
Zip Code
01655