Pulmonary hypertension is characterized by increased pulmonary vascular resistance, in part, due to thickening of pulmonary arterial walls. Vascular thickness is influenced by smooth muscle cell (SMC) proliferation and apoptosis. Mechanisms that regulate pulmonary vascular SMC apoptosis, however, have not been defined. Lack of such knowledge interferes with the development of new strategies to prevent and/or treat pulmonary hypertension. My long-range goal is to identify the mechanisms of apoptotic regulation in pulmonary vascular SMC to develop apoptosis-based therapeutic strategies to reduce vascular thickness. The objective of this competitive renewal application is to evaluate specifically the mechanism of gene transcription of a major anti-apoptotic protein Bcl-xL. The central hypothesis is that GATA-4 regulates Bcl-xL gene transcription. The hypothesis has been formulated on the basis of preliminary data, which suggest that i) the region of bcl-x gene promoter which regulates gene transcription of anti-apoptotic isoform Bcl-xL is active in pulmonary artery SMC, ii) this region contains binding sites for GATA-4 which is a pulmonary-specific SMC regulator, and iii) regulators of pulmonary hypertension alters GATA-4 activity, Bcl- xL expression, and apoptosis. The rationale for the proposed research is that, once knowledge of the regulation of pulmonary vascular SMC apoptosis has been obtained, it will lead to new strategies that can be used to treat pulmonary hypertension. I am uniquely prepared to undertake the proposed research because techniques and reagents to study apoptosis and gene regulation are available in my laboratory. The objective of the application will be accomplished by pursuing three specific aims: 1) Characterize the regulation of basal Bcl-xL gene transcription in smooth muscle from normal and remodeled pulmonary arteries, 2) Identify mechanisms for the induction of Bcl-xL gene transcription, and 3) Define the mechanisms and functions of downregulation of Bcl-xL expression in normal and remodeled pulmonary arteries. The proposed work is innovative because it will investigate novel apoptotic mechanisms using a unique adenovirus-based reporter system. It is my expectation that GATA-4 regulates Bcl-xL expression and controls apoptosis. These results will be significant because they are expected to provide new agents against pulmonary hypertension. In addition, the results will fundamentally advance the field of lung biology. ? ? ?
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