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， 在睡眠期间，并引起动脉血氧饱和度下降的反复发作 血液（缺氧）。 长期而言，OSA综合征可导致许多浆液性 心血管问题，包括全身性动脉高血压。 有 有证据表明，阻塞性睡眠呼吸暂停引起的高血压是神经源性的， 从氧化学感受器细胞在颈动脉体，并涉及 外周交感神经系统内的儿茶酚胺能细胞， 肾上腺髓质 该申请提出，间歇性低氧 刺激这些组织中的基因表达，这可能与 OSA相关高血压的发病机制。 都支持这一看法 先前的研究发现，短时间（<1小时）的持续缺氧刺激 几个基因在氧敏感的1型细胞中的表达， 颈动脉体，包括酪氨酸羟化酶（TH），限速酶， 儿茶酚胺合成 增强的儿茶酚胺生物合成 交感神经系统是高血压的潜在发病机制。 的 目前的研究将测试的假设，非常短暂的事件（20秒）， 再次发生的缺氧足以增加颈动脉中的基因表达 体、上级颈神经节和肾上腺。 据推测 间歇性缺氧调节这些组织中的基因表达， 导致阻塞性睡眠呼吸暂停综合征引起的高血压。 具体目标1将侧重于 表征间歇性缺氧对已知缺氧的影响- 调节基因已牵连在高血压，即TH和一些 其已知的转录调节因子包括c-fos、junB和CREB。 这 目的还将检验间歇性诱导基因表达的假设， 上级颈神经节和肾上腺的缺氧需要突触 源自颈动脉体的输入。 进一步假设， 许多基因和蛋白质的协调调节介导了细胞内 对间歇性缺氧等复杂刺激的反应。 这种可能性 将在具体目标2中进行探索，重点是识别基因 颈动脉体、上级颈神经节、颈动脉体、颈 使用独特的cDNA文库和高通量基因组学 (cDNA微阵列）和蛋白质组学（2-D蛋白质凝胶和质谱仪） 分析. 这项研究的结果可能会提供新的见解， 间歇性低氧对基因表达的调节作用及可能的机制 介导OSA诱导的高血压发病机制的靶点。

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.