STUDY OF ROLES OF TACHYKININS IN THE NERVOUS SYSTEM

速激肽在神经系统中的作用研究

• 批准号: 3083628
• 负责人: CLIFFORD W SHULTS
• 金额: $ 6.55万
• 依托单位: UNIVERSITY OF CALIFORNIA, SAN DIEGO
• 依托单位国家: 美国
• 财政年份: 1985
• 资助国家: 美国
• 起止时间: 1985-08-01 至 1990-07-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/3083628
• 关键词: Alzheimer's disease; Huntington's disease; Parkinson's disease; astrocytes; autoradiography; brain mapping; cyclic AMP; norepinephrine; radioimmunoassay; tissue /cell culture

Substance P (SP) has been shown in certain systems to modulate the actions of acetylcholine and norepinephrine. Although modulation of the effects of classic neurotransmitters may be one of the important functions of SP in the nervous system, the mechanisms by which it does this are unknown. SP was the first member of the tachykinin family to be identified in the brain. Recently two new tachykinins, neurokinin A (NKA) and neurkinin B (NKB), were identified in mammalian nervous tissue. Detailed anatomical distributions of NKA and NKB and their binding sites remains unknown. It is also not known whether NKA and NKB have modulatory actions of their own. Polyclonal antisera will be raised in rabbits against NKA and NKB, and their distributions in rat brain will be studied by both microdissection combined with radioimmunoassay and by immunshistochemistry. We will determine if NKA and NKB ae present in human brain and, if so, in which regions. Because SP is reduced in Parkinson's, Huntington's, and Alzheimer's diseases, we will determine whether levels of NKA and NKB are also changed in these diseases. The binding sites for NKA and NKB in rat brain will be characterized by membrane and slice binding techniques and localized by autoradiography. In cultured rat astrocytes SP augments norepinephrine's stimulation of cAMP formation without stimulating cAMP production itself. Cultured astrocytes will be developed as a system to systematically study mechanisms of tachykinin modulation of beta adrenergic stimulated increase in cAMP. Binding studies both in intact cells and with membranes will be performed to assess the effects of tachykinins on the affinity and number of beta adrenergic receptors. The effect of tachykinins on the activity of adenylate cyclase, phosphodiesterase, and phosphoinositide metabolism will also be studied. Our findings from astrocytes will be applied to brain regions in which significant levels of tachykinins or their binding sites are found to study the biochemical mechanism of tachykinin action in the brain. One member of the tachykinin family, SP, is acknowledged to play a significant role in the extrapyramidal and nociceptive systems. SP has also been shown to be decreased in certain degenerative neurological diseases. The proposed studies will elucidate regions of the brain in which tachykinins are involved in neurological function and dysfunction and biochemical mechanisms by which they act.

P物质（SP）已被证明在某些系统中调节作用 乙酰胆碱和去甲肾上腺素 虽然调节的效果 经典的神经递质可能是SP的重要功能之一， 神经系统，其机制尚不清楚。 SP 是第一个被发现的速激肽家族成员， 个脑袋 最近发现了两种新的速激肽，即神经激肽A（neurokinin A，NKA）和神经激肽B (NKB)，在哺乳动物神经组织中被鉴定。 详细的解剖 NKA和NKB的分布及其结合位点仍然未知。 它 也不知道NKA和NKB是否具有它们自己的调节作用。 将在兔中产生抗NKA和NKB的多克隆抗血清， 通过显微解剖和组织化学方法研究它们在大鼠脑内的分布 结合放射免疫分析和免疫组化。 我们将 确定NKA和NKB是否存在于人脑中，如果存在， 地区 因为帕金森氏症、亨廷顿氏症和 阿尔茨海默病，我们将确定是否NKA和NKB的水平， 在这些疾病中也发生了变化。大鼠NKA和NKB的结合位点 大脑将通过膜和切片结合技术表征， 通过放射自显影定位。 SP增强去甲肾上腺素对大鼠星形胶质细胞cAMP的刺激作用 而不刺激cAMP本身的产生。 培养的星形胶质细胞 将作为一个系统，系统地研究机制， β肾上腺素能的速激肽调节刺激cAMP增加。 将在完整细胞和膜中进行结合研究 为了评估速激肽对β受体的亲和力和数量的影响， 肾上腺素能受体 速激肽对细胞增殖活性的影响 腺苷酸环化酶、磷酸二酯酶和磷酸肌醇代谢将 也被研究。 我们在星形胶质细胞上的发现将应用于大脑 其中显著水平的速激肽或其结合位点 被发现研究速激肽作用的生化机制， 个脑袋 速激肽家族的一个成员，SP，被认为是发挥作用， 在锥体外系和伤害感受系统中起重要作用。 SP具有 也被证明在某些退行性神经系统疾病中 疾病 拟议的研究将阐明大脑的区域， 其中速激肽参与神经功能和功能障碍， 生物化学机制，它们的作用。