Intermittent Hypoxia-Induced Hypertension: Roles of Angiotensin and Chloride Transport in the Lamina Terminalis.

间歇性缺氧引起的高血压：血管紧张素和氯离子转运在终层中的作用。

• 批准号: 9096158
• 负责人: J Thomas Cunningham
• 金额: $ 45.93万
• 依托单位: UNIVERSITY OF NORTH TEXAS HLTH SCI CTR
• 依托单位国家: 美国
• 财政年份: 2008
• 资助国家: 美国
• 起止时间: 2008-09-05 至
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/9096158
• 关键词: Affect; Angiotensin II; Angiotensin Receptor; Angiotensin Type 1a Receptor; Angiotensins; Animal Experiments; Animal Model; Binding Sites; Biological Markers; Blood Pressure; Brain; Cardiovascular Diseases; Chloride Ion; Chlorides; Chronic; Data; Development; Diagnosis; Disease; Electrophysiology (science); Functional disorder; Gene Expression; Gene Targeting; Glutamates; Hypertension; Hypothalamic structure; Hypoxemia; Hypoxia; In Vitro; Injection of therapeutic agent; Ischemia; Lamina Terminalis; Lesion; Mediating; Messenger RNA; Modality; Modeling; Muscimol; Nerve; Neurons; Pathogenesis; Pathway interactions; Patients; Peptidyl-Dipeptidase A; Phosphotransferases; Play; Population; Potassium Chloride; Predisposition; Proteins; Publications; Rattus; Renin-Angiotensin System; Research; Role; Site; Sleep; Sleep Apnea Syndromes; Sodium; Stroke; Subfornical Organ; System; Testing; Viral Vector; Work; base; cardiovascular disorder risk; gamma-Aminobutyric Acid; in vivo; insight; knock-down; laser capture microdissection; neurotransmission; optogenetics; paraventricular nucleus; patch clamp; preoptic nucleus; programs; promoter; research study; small hairpin RNA; symporter

Summary – Project 2 Our working hypothesis, which is based on our publications and our preliminary data, is that the median preoptic nucleus (MnPO) contributes to CIH hypertension due to activity dependent changes in gene expression mediated by FosB that are driven by circulating angiotensin II (ANG II) working through the subfornical organ (SFO). The MnPO influences sympathetic nerve activity through its projection to the paraventricular nucleus of the hypothalamus. We have identified several putative FosB target genes in MnPO that may contribute to CIH hypertension including angiotensin converting enzyme 1 (ACE1), and based on our preliminary data the angiotensin receptor type 1a (AT1aR). Together these FosB target genes may drive the MnPO contribution to CIH hypertension through their possible interaction with the sodium-potassium-chloride co-transporter 1 (NKCC1). Specific Aim 1: to determine the contribution of ACE1 in the MnPO to CIH mediated hypertension. Hypothesis: Increased expression of ACE1 in the MnPO is necessary for CIH hypertension Specific Aim 2: to test the role of increased AT1aR expression in the MnPO in CIH hypertension. Hypothesis: Increased AT1aR expression contributes to enhanced activation of the MnPO during CIH. Specific Aim 3: to determine the role of NKCC1 in the MnPO in CIH hypertension. Hypothesis: Increased expression and activity of NKCC1 reduces the inhibitory effects of GABA in the MnPO leading to greater sympathoexcitation during CIH. These hypotheses will be tested using an integrative approach combining whole animal experiments employing virally mediated shRNA knockdown, in vivo sympathetic nerve and single unit recording, in vitro patch clamp recording, and laser capture microdissection with qRT-PCR. Optogenetic approaches will be used to test the role of the SFO-MnPO pathway in CIH hypertension using promoters that are specific for glutamate expressing neurons.

摘要-项目2 我们的工作假设，这是基于我们的出版物和我们的初步数据，是中位数 视前核（MnPO）由于基因活性依赖性变化而导致CIH高血压 由FosB介导的表达，由循环血管紧张素II（ANG II）驱动， 穹窿下器官（SFO）。MnPO通过投射到交感神经来影响交感神经活动。 下丘脑室旁核。我们已经在MnPO中鉴定了几个假定的FosB靶基因， 包括血管紧张素转换酶1（ACE 1），并根据我们的研究， 血管紧张素受体1a型（AT 1aR）。这些FosB靶基因一起可以驱动 MnPO通过与钠-钾-氯化物的可能相互作用对CIH高血压的贡献 共转运蛋白1（NKCC 1）。 具体目标1：确定MnPO中ACE 1对CIH介导的高血压的贡献。 假设：MnPO中ACE 1表达增加是CIH高血压所必需的 具体目的2：检测MnPO中AT 1aR表达增加在CIH高血压中的作用。 假设：AT 1aR表达的增加有助于CIH期间MnPO的激活增强。 具体目标3：确定NKCC 1在CIH高血压中MnPO中的作用。 假设：NKCC 1的表达和活性增加降低了GABA在MnPO中的抑制作用。 导致CIH时更强的交感神经兴奋 这些假设将使用结合整体动物实验的综合方法进行测试 采用病毒介导的shRNA敲低，体内交感神经和体外单个单位记录， 膜片钳记录和用qRT-PCR的激光捕获显微切割。将使用光遗传学方法 使用谷氨酸特异性启动子检测SFO-MnPO通路在CIH高血压中的作用 表达神经元。