NEUROPEPTIDASES AND CAROTID BODY FUNCTIONS

神经肽酶和颈动脉体功能

• 批准号: 6030625
• 负责人: Ganesh K Kumar
• 金额: $ 21.64万
• 依托单位: CASE WESTERN RESERVE UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 1995
• 资助国家: 美国
• 起止时间: 1995-06-07 至 2001-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6030625
• 关键词: acetylcholinesterase; carotid body; chemical structure function; enkephalins; enzyme activity; hemorrhagic shock; high performance liquid chromatography; hypercapnia; hyperoxia; hypoxia; immunoelectron microscopy; laboratory rat; microspectrophotometry; neprilysin; radioimmunoassay; superior cervical ganglion; sympathectomy; western blottings

The carotid bodies transduce changes in the levels of arterial oxygen, carbon dioxide and hydrogen ion concentrations into action potential encoded nerve signals. This transduction process is complex and believed to involve several neurochemicals including neuropeptides. Neuropeptidases, viz., neutral endopeptidase (NEP), a soluble endopeptidase (sNEP), and endothelin converting enzyme (ECE)-like activity occur in the carotid body and they involve in the metabolism of neuropeptides in the chemoreceptor tissue. More importantly, inhibition of these enzymes by phosphoramidon both in vivo and in vitro appears to potentiate not only the carotid body activity but also its response to the physiological stimulus, hypoxia. These observations suggest that NEP, sNEP and ECE-like activity may play hitherto undefined important functional roles in the carotid body. This investigation, specifically, addresses the molecular characterization and regulation of NEP, sNEP and ECE and their importance in the functions of the carotid body. Our hypothesis is that: a) Peptidases regulate the synthesis and degradation of neuropeptides in the carotid body, and that the activity and peptidases levels are differentially altered by hypoxia. b) Hypoxia induced alteration of peptidases involves dopaminergic receptors resulting in changes in the peptide levels of the carotid body. c) The changes in neuropeptides, in turn, contribute to the altered sensitivity of the carotid body to hypoxia. Studies proposed in Specific Aim 1 will determine the influence of short-term hypoxia on neuropeptidases of the carotid body. In Specific Aim 2, the cellular mechanism(s) associated with the regulation of neuropeptidases of the carotid body by short-term hypoxia will be investigated. The effect of long-term hypoxia on the activity and expression of NEP, sNEP and ECE- like activities of the carotid body will be examined in studies of Specific Aim 3. In Specific Aim 4, we will determine the influence of dopamine, and dopaminergic antagonists on neuropeptidases and neuropeptide metabolism of the carotid body. It is anticipated that the proposed studies will provide clues as to the role of phosphoramidon- sensitive enzymes in the functions of the carotid body. These studies may also yield new information in the development of enzyme based therapeutic agents in the treatment of hypoxemia, associated with high altitude adaptation and chronic obstructive lung diseases.

颈动脉体反映动脉血氧水平的变化， 二氧化碳和氢离子浓度转化为动作电位 编码的神经信号 这种转导过程是复杂的， 据信涉及包括神经肽在内的几种神经化学物质。 神经肽酶，即，中性内肽酶（NEP），一种可溶性 内肽酶（sNEP）和内皮素转化酶（ECE）样 活动发生在颈动脉体，它们参与代谢 化学感受器组织中的神经肽。 更重要的是， 体内和体外Phosphoramidon对这些酶抑制作用 似乎不仅增强了颈动脉体的活动， 对生理刺激缺氧的反应 这些观察结果 提示NEP、sNEP和ECE样活性可能起迄今未定义作用 在颈动脉体中的重要功能作用。 这次调查 特别是，解决了分子表征和调节 新经济政策、新经济政策和早期教育的作用及其在联合国 颈动脉体 我们的假设是：a）肽酶调节 颈动脉体中神经肽的合成和降解， 活性和肽酶水平被不同地改变， 缺氧 B）缺氧诱导的肽酶改变涉及 多巴胺能受体的变化，导致的肽水平的变化， 颈动脉体c）神经肽的变化反过来又有助于 颈动脉体对缺氧的敏感性改变 研究 具体目标1中提出的建议将确定短期影响 缺氧对颈动脉体神经肽酶的影响。 具体目标2 与神经肽酶调节相关的细胞机制 将研究短期缺氧对颈动脉体的影响。 的 长期低氧对大鼠脑内NEP、sNEP活性及表达的影响 和ECE样活性的颈动脉体将在研究中进行检查 具体目标3。 在具体目标4中，我们将确定 多巴胺和多巴胺能拮抗剂对神经肽酶和 颈动脉体的神经肽代谢。预计该 拟议中的研究将为磷酰胺的作用提供线索， 敏感酶在颈动脉体的功能。 这些研究 也可能产生新的信息，在酶的发展为基础的 用于治疗低氧血症的治疗剂， 高原适应和慢性阻塞性肺疾病。