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NEUROPEPTIDASES AND CAROTID BODY FUNCTIONS

神经肽酶和颈动脉体功能

基本信息

批准号：
6183215
负责人：
Ganesh K Kumar
金额：
$ 22.29万
依托单位：
CASE WESTERN RESERVE UNIVERSITY
依托单位国家：
美国
项目类别：
财政年份：
1995
资助国家：
美国
起止时间：
1995-06-07 至 2002-06-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/6183215
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

项目摘要

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.

颈动脉体传导动脉氧水平的变化，将二氧化碳和氢离子浓度转化为动作电位编码的神经信号。这个转导过程很复杂据信涉及多种神经化学物质，包括神经肽。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) 样颈动脉体发生活动并参与新陈代谢化学感受器组织中的神经肽。更重要的是，磷酰胺在体内和体外对这些酶的抑制作用似乎不仅能增强颈动脉体的活性，还能增强其对生理刺激、缺氧的反应。这些观察表明 NEP、sNEP 和 ECE 样活动可能发挥迄今为止未定义的作用在颈动脉体中发挥重要的功能作用。此次调查，具体来说，解决了分子表征和调控 NEP、sNEP 和 ECE 及其在职能中的重要性颈动脉体。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的改变有差异缺氧。 b) 缺氧引起的肽酶改变涉及多巴胺能受体导致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中提出的将决定短期的影响颈动脉体神经肽酶缺氧。在具体目标 2 中，与神经肽酶调节相关的细胞机制将调查短期缺氧对颈动脉体的影响。这长期缺氧对NEP、sNEP活性及表达的影响研究将检查颈动脉体的 ECE 样活动具体目标 3 的影响。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的影响颈动脉体的神经肽代谢。预计拟议的研究将为磷酰胺的作用提供线索颈动脉体功能中的敏感酶。这些研究也可能在基于酶的开发中产生新的信息治疗与高氧相关的低氧血症的治疗剂海拔适应和慢性阻塞性肺疾病。