REGULATION OF GENE EXPRESSION IN INTERMITTENT HYPOXIA

阻塞性睡眠呼吸暂停(OSA)是一种相对常见的疾病， 以反复发作的上呼吸道阻塞为特征 并导致动脉血氧减饱和的反复发作 血液(缺氧)。慢性阻塞性睡眠呼吸暂停综合征可导致许多浆液性疾病 心血管问题，包括系统性动脉高血压。的确有 有证据表明OSA诱发的高血压是神经原性的，它是由 来自颈动脉小体中的氧化学感受器细胞，并涉及 周围交感神经系统内的儿茶酚胺能细胞和 肾上腺髓质。这一应用表明间歇性低氧 刺激这些组织中的基因表达，这可能参与了 阻塞性睡眠呼吸暂停相关高血压的发病机制。这是由支持的 先前的研究发现，短暂的持续缺氧(1小时)会刺激 氧敏感1型细胞中几个基因的表达 颈动脉小体，包括酪氨酸羟化酶(TH)，这是 儿茶酚胺合成。增强体内儿茶酚胺的生物合成 交感神经系统是高血压的一种潜在机制。这个 目前的研究将检验这一假设，即非常短的插曲(20秒) 反复发生的低氧足以增加颈动脉中的基因表达 身体、颈上神经节和肾上腺。这是假设的 间歇性低氧调节这些组织中的基因表达 结果OSA诱发高血压。具体目标1将重点放在 表征间歇性低氧对已知低氧的影响- 与高血压有关的受调控基因，即TH和一些 其已知的转录调控因子包括c-fos、JunB和CREB。这 AIM还将测试间歇性诱导的基因表达的假设 颈上神经节和肾上腺的缺氧需要突触 起源于颈动脉小体的输入。进一步假设 许多基因和蛋白质的协调调节调节细胞 对间歇性缺氧等复杂刺激的反应。这种可能性 将在特定目标2中进行探索，该目标将侧重于识别基因 和蛋白在颈动脉体颈上神经节中的表达 和肾上腺使用独特的cDNA文库和高通量基因组学 (基因芯片)和蛋白质组学(二维蛋白质凝胶和质谱仪) 分析。这项研究的发现可能会提供关于 间歇性低氧在基因表达调控中的作用及可能 阻塞性睡眠呼吸暂停低密度脂蛋白诱导高血压发病机制的研究

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.