NEUROPEPTIDASES AND CAROTID BODY FUNCTIONS

神经肽酶和颈动脉体功能

• 批准号: 2693324
• 负责人: Ganesh K Kumar
• 金额: $ 20.01万
• 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/2693324
• 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.

颈动脉小体传递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，而且 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)，一种可溶性的 内肽酶(SNEP)和内皮素转换酶(ECEs)样蛋白 活动发生在颈动脉小体，参与新陈代谢。 化学感受器组织中的神经肽。更重要的是， 磷酰胺对这些酶的体内外抑制作用 似乎不仅增强了颈动脉体部的活动，而且还 对生理刺激、缺氧的反应。这些观察结果 表明NEP、SNEP和欧洲经委会类活动可能发挥迄今未确定的作用 在颈动脉小体中扮演重要的功能角色。这次调查， 具体地说，解决了分子特征和调节 新伙伴关系、新伙伴关系和欧洲经委会及其在欧洲经委会职能中的重要性 颈动脉小体。我们的假设是：a)肽酶调节 颈动脉小体神经肽的合成和降解 活性和多肽酶水平由不同的 缺氧。B)低氧引起的多肽酶的改变包括 多巴胺能受体引起脑内神经节细胞多肽水平的变化 颈动脉小体。C)神经肽的变化反过来又有助于 颈动脉小体对缺氧的敏感性改变。研究 提出的具体目标1将决定短期内的影响 低氧对颈动脉体神经肽酶的影响。在具体目标2中， 神经肽酶调控的细胞机制(S) 对颈动脉体受短期低氧影响的情况将进行调查。这个 长期低氧对NEP、SNEP活性及表达的影响 将在研究中检查颈动脉小体的ECE样活动 具体目标3。在具体目标4中，我们将确定影响 多巴胺和多巴胺能拮抗剂对神经肽酶和 颈动脉小体的神经肽代谢。据预计， 拟议的研究将为磷酰胺的作用提供线索- 颈动脉小体功能中的敏感酶。这些研究 也可能在基于酶的开发中产生新的信息 治疗药物治疗低氧血症，与高氧血症相关 高原适应与慢性阻塞性肺疾病。