CSF and the central chemical control of breathing

CSF 和呼吸的中央化学控制

• 批准号: 9261557
• 负责人: Aihua Li
• 金额: $ 38.33万
• 依托单位: DARTMOUTH COLLEGE
• 依托单位国家: 美国
• 财政年份: 1994
• 资助国家: 美国
• 起止时间: 1994-07-01 至 2019-04-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9261557
• 关键词: Affect; Air; Allatostatin; Animals; Automobile Driving; Blood Pressure; Breathing; CCR; Carbon Dioxide; Cell Nucleus; Chemicals; Chemoreceptors; Designer Drugs; Development; Environmental air flow; Enzymes; Essential Hypertension; Goals; Health; Hypertension; Hypothalamic structure; Inbred SHR Rats; Injection of therapeutic agent; Lateral; Link; Measurement; Medical; Microinjections; Mission; Mus; Nerve; Neurons; Outcome; REM Sleep; Rattus; Receptor Inhibition; Regulation; Rest; Rodent; Role; Serotonin; Site; Sleep; Small Interfering RNA; System; TPH2; Testing; Transfection; Transgenic Mice; Transgenic Organisms; Viral; Wakefulness; blood pressure regulation; designer receptors exclusively activated by designer drugs; experimental study; hypocretin; normotensive; prepro-orexin; public health relevance; receptor; response; small hairpin RNA

DESCRIPTION (provided by applicant): This project will test the hypothesis that specific neurons in three neuroanatomical sites important in the ventilatory CO2 chemoreflex also participate in the regulation of sympathetic nerve activity (SNA) and blood pressure (BP) in normal rats and mice, and in Spontaneously Hypertensive Rats (SHR). The three central chemoreceptor sites (and neurons) are: 1) orexin neurons of the lateral hypothalamus (LHA); 2) Phox2b- expressing neurons of the retrotrapezoid nucleus (RTN); and 3) serotonergic (5-HT) neurons of the medullary raphe (MR). The measurements, obtained in unanesthetized rodents during wakefulness, REM and NREM sleep include ventilation, SNA and BP at rest while breathing air and in response to breathing 5% CO2. The experiments involve focal disruption of: 1) orexin neuron function by siRNA induced inhibition of prepro-orexin in the lateral hypothalamus, 2) Phox2b-expressing neurons of the RTN by viral transfection of a PRS8/allatostatin receptor construct followed by subsequent allatostatin injection to inhibit the neurons reversibly; 3) 5-HT neuron function in: a) mice by transgenic insertion of the inhibitory HM4D receptor in all 5-HT neurons or in 5-HT neurons derived from rhombomeres 3 and 5 (DREADD: Designer Receptor Activated by Designer Drug), and b) rats by siRNA/shRNA to block activity of tryptophan hydroxylase 2 the enzyme for 5-HT synthesis (TPH2). In addition, the experiments involve antagonism of orexin receptors by almorexant administered systemically and focally within the medullary raphe and retrotrapezoid nucleus. The major goals are to further the understanding of the link between chemoreception and blood pressure regulation, and to begin to relate this understanding to the development of some forms of hypertension, which has relevance to the mission of the agency and to medical practice.

描述（由申请人提供）：该项目将检验以下假设：在通气CO2 ChemoreFlex中重要的三个神经解剖部位的特定神经元也参与了正常大鼠和小鼠的交感神经活性（SNA）和血压（BP）的调节，以及自发性下降大鼠（SHR）。下丘脑（LHA）的三个中央化学感受器位点（和神经元）是：1）OREXIN神经元； 2）逆转录核（RTN）的Phox2b-表达神经元； 3）髓质raphe（MR）的血清素能（5-HT）神经元。在清醒期间以一式化啮齿动物获得的测量值，REM和NREM睡眠包括静止的通风，SNA和BP，同时呼吸空气以及呼吸5％CO2。该实验涉及以下：1）通过siRNA诱导抑制前蛋白质在下丘脑中抑制前蛋白的局灶性破坏，2）通过病毒转染Prs8/allatotototor构建体的病毒转染，prs8/allatostatin受体构建体，随后的ynaTostostIntor nection neurons recection to recretion the neurons recection to recection in Neurons recection to re nection in Neurons rectience， 3) 5-HT neuron function in: a) mice by transgenic insertion of the inhibitory HM4D receptor in all 5-HT neurons or in 5-HT neurons derived from rhombomeres 3 and 5 (DREADD: Designer Receptor Activated by Designer Drug), and b) rats by siRNA/shRNA to block activity of tryptophan hydroxylase 2 the enzyme for 5-HT synthesis （TPH2）。此外，实验涉及甲素内和局部在髓质raphe和腹膜核核中施用甲脱甲蛋白受体的拮抗作用。主要目标是进一步理解化学感受与血压调节之间的联系，并开始将这种理解与某些形式的高血压的发展联系起来，这与机构的使命和医疗实践有关。