Pulmonary vascular disease constitutes a major cause of mortality, morbidity and healthcare expenditure. Although the underlying causes are mutifactorial, this condition is generally characterized by increased pulmonary vascular resistance, which develops on the basis of both vasoconstriction and arterial vascular remodeling. Within this context, pathobiologic changes in the pulmonary endothelium are understood to playa central role in the development of both of these characteristic disease features. Studies of pathologic material from patients have demonstrated dysregulated expression of factors relevant to vasomotor tone and vascular wall remodeling. It is clear. however, that a fuller understanding of these pulmonary endothelial abnormalities will be required to allow rational interventional strategies. In this regard, methods allowing specific and directed perturbations in gene expression profiles within pulmonary endothelium would potentially provide unique insight into disease pathophysiology. On this basis, it would be desirable to develop technologies to achieve the goal of transient alterations in gene expression patterns selectively within pulmonary endothelium. Such gene-based methods would allow rational analysis of candidate genes with respect to their role in the pathobiology of this condition. Of note, these same methods would potentially allow directed therapeutic interventions. We have recently developed methods to alter the tropism of Ad vectors. These modifications have allowed the achievement of cell-specific gene delivery to pulmonary vascular endothelium in vivo after systemic vascular administration of the vector. We will use these modified Ad vectors to deliver relevant genes to the pulmonary endothelium in rat models of pulmonary hypertension and thrombosis, as a means to discover new insights into the pathophysiology of pulmonary hypertension. In these analyses we will asses the impact of gene delivery on pulmonary vascular pressures, vascular remodeling and thrombosis. In addition, it is our hypothesis that we can further improve the targeting properties of adenoviral vectors by genetic means, thereby improving the efficiency and specificity for I pulmonary endothelial markers and generating agents of potential clinical utility.

Agency
National Institute of Health (NIH)
Institute
National Heart, Lung, and Blood Institute (NHLBI)
Type
Research Project (R01)
Project #
1R01HL067962-01
Application #
6364186
Study Section
Experimental Cardiovascular Sciences Study Section (ECS)
Program Officer
Garfinkel, Susan J
Project Start
2001-08-01
Project End
2005-07-31
Budget Start
2001-08-01
Budget End
2002-07-31
Support Year
1
Fiscal Year
2001
Total Cost
$376,851
Indirect Cost
Name
University of Alabama Birmingham
Department
Internal Medicine/Medicine
Type
Schools of Medicine
DUNS #
004514360
City
Birmingham
State
AL
Country
United States
Zip Code
35294
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