? Primary pulmonary hypertension (PPH) is rare, but often fatal, with increased incidence in users of appetite suppressants. It is characterized by increased lung vascular resistance due to thickening of pulmonary arterial walls. The cellular mechanisms that regulate smooth muscle cell number, however, have not been defined. Lack of such knowledge interferes with the development of new therapeutic strategies that are designed to prevent and/or treat this condition. My long-range goal is to identify the mechanisms for the regulation of apoptosis in human pulmonary artery smooth muscle cells (HPASMC). The objective of this application is to evaluate specifically the role of GATA transcription factors. The central hypothesis of the application is that GATA factors regulate apoptosis and survival. The hypothesis has been formulated on the basis of strong preliminary data, which suggest that i) GATA-4 and -6 are expressed in HPASMC, ii) apoptotic stimuli downregulate the GATA activity, and iii) serotonin and endothelin-1 exert anti-apoptotic signaling and enhance the GATA activity. The rationale for the proposed research is that, once knowledge of the mechanisms that regulate the lung vascular medial thickening has been obtained, it will lead to new strategies that can be used to prevent and/or treat PPH, thereby reducing the morbidity and mortality that are associated with this condition. I am uniquely prepared to undertake the proposed research because my lab has been studying GATA factors, and many of the techniques and reagents are already available. The central hypothesis will be tested and the objective of the application accomplished by pursuing two specific aims: 1) Identify the mechanisms of HPASMC apoptosis induced by nitric oxide and retinoic acid, and 2) Determine the mechanisms by which serotonin and endothelin-1 exert anti-apoptotic signaling. The proposed work is innovative, because it will investigate novel transcription factors in lung using an approach that has been used in the studies of cardiac muscle. It is my expectation that GATA factors are involved in the regulation of apoptosis of HPASMC. These results will be significant because they are expected to provide new agents for preventative and therapeutic interventions of PPH. In addition, it is expected that the results will fundamentally advance the field of lung cell biology. ? ?
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