REGULATION OF GENE EXPRESSION IN INTERMITTENT HYPOXIA

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Obstructive sleep apnea (OSA) is a relatively common disorder that is characterized by repetitive episodes of upper-airway obstruction that occur during sleep and cause repetitive episodes of oxygen desaturation of arterial blood (hypoxia). Chronically, OSA syndrome can result in a number of serous cardiovascular problems including systemic arterial hypertension. There is evidence that the OSA-induced hypertension is neurogenic, that it emanates from the oxygen chemoreceptor cells in the carotid body, and involves the catecholaminergic cells within the peripheral sympathetic nervous system and adrenal medulla. This application proposes that intermittent hypoxia stimulates gene expression in these tissues, and that this may be involved in the pathogenesis of hypertension associated with OSA. This is supported by the previous finding that brief periods (<1hr) of sustained hypoxia stimulates expression of several genes in the oxygen-sensitive type 1 cells of the carotid body, including tyrosine hydroxylase (TH), the rate-limiting enzyme in catecholamine synthesis. Enhanced catecholamine biosynthesis in the sympathetic nervous system is a potential mechanism for hypertension. The present research will test the hypothesis that very brief episodes (20 sec) of re-occurring hypoxia are sufficient to increase gene expression in the carotid body, superior cervical ganglion, and the adrenal gland. It is hypothesized that intermittent hypoxia regulates gene expression in these tissues and results in the OSA-induced hypertension. Specific Aim 1 will focus on the characterizing the effects of intermittent hypoxia on a known hypoxia- regulated gene that has been implicated in hypertension, namely TH and some of its known transcriptional regulators, including c-fos, junB, and CREB. This aim will also test the hypothesis that gene expression induced by intermittent hypoxia in the superior cervical ganglion and adrenal gland requires synaptic input that originates in the carotid body. It is further hypothesized that coordinate regulation of many genes and proteins mediates the cellular response to such a complex stimulus as intermittent hypoxia. This possibility will be explored in Specific Aim 2, which will focus on identifying the gene and protein expression pattern in the carotid body, superior cervical ganglion and adrenal gland using unique cDNA libraries and high-throughout genomics (cDNA microarray) and proteomics (2-D protein gels and mass spectrometer) analysis. The findings from this study may provide new insight concerning the role of intermittent hypoxia on regulation of gene expression and possible targets for mediating the pathogenesis of OSA-induced hypertension.