Abnormally increased expression of platelet thromboxane receptors results in platelet hypersensitivity and increased thrombogenecity in acute myocardial infarction. We and others have shown that platelet development and thromboxane receptor expression are subject to regulatory control by circulating humoral factors. The long term goal of our studies is to identify and define the physiologically significant regulatory mechanisms for normal and abnormal platelet development and thromboxane receptor expression, focusing on the role of platelet agonists as potential modifiers of platelet development from precursor megakaryoblasts. In the current proposal we will define the events which transduce megakaryocytic differentiation in a comparative analysis of thrombin, thromboxane, and alpha2 adrenergic signaling. These three agonists were selected based on their potential importance as in vivo stimuli and because we have identified unique signaling characteristics for each in cultured platelet-like cells.
In Specific Aim #1 we will characterize receptor-G protein coupling and cell signal activation in cultured megakaryoblasts and transfected cell lines.
In Specific Aim #2 we will determine which receptor-stimulated cell signals are important in initiating the molecular program of megakaryocytic differentiation, focusing on thromboxane receptor gene expression.
In specific Aim #3 we will delineate the regulatory determinants of thromboxane receptor gene expression by analyzing its promoter, thereby identifying nuclear transcription factors which have the potential to modulate platelet development. This combined approach of characterizing agonist-mediated cell signaling and gene expression, while identifying transcriptional controls for platelet development, is expected to further elucidate the role of abnormal platelet development in acute myocardial ischemia and other thrombooclusive syndromes.
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