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Analytical Methods for Investigating Peptide Transport

研究肽转运的分析方法

基本信息

批准号：
7441307
负责人：
Susan M Lunte
金额：
$ 35.05万
依托单位：
UNIVERSITY OF KANSAS LAWRENCE
依托单位国家：
美国
项目类别：
财政年份：
2002
资助国家：
美国
起止时间：
2002-03-18 至 2008-06-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/7441307
关键词：
Adverse effects Affect Agonist Alzheimer&apos s Disease Amides Amino Acid Neurotransmitters Analgesics Animals Area Astrocytes Attention Autopsy Back Behavior Behavior monitoring Binding Biological Blood - brain barrier anatomy Bos taurus Brain C-terminal Catecholamines Cattle Cells Clinical Cocaine Dependence Coculture Techniques Codeine Detection Development Disease Dopamine Drug Addiction Drug Industry Dynorphin A Dynorphins Electrophoresis Endothelial Cells Excitatory Amino Acids Exhibits Extracellular Space Glutamates Goals Grant Hormones In Vitro Investigation Lead Ligands Limb structure Marketing Measurement Mediating Mental Depression Metabolism Methodology Microchip Electrophoresis Microdialysis Monitor Mood Disorders Morphine N-Methyl-D-Aspartate Receptors Neuromodulator Neurons Neuropeptides Neurotransmitters Nitric Oxide Numbers Organism Pain Paralysed Parents Patients Peptide Fragments Peptide Metabolism Peptide Transport Peptides Peripheral Pharmaceutical Preparations Physiological Play Process Property Rattus Reporting Research Role Sampling Scientist Sheep Site Substance P Symptoms System Techniques Telemetry Therapeutic Therapeutic Effect Tissues addiction analog analytical method awake base desire in vivo interest kappa opioid receptors microchip neurochemistry neurotoxic neurotransmitter release painful neuropathy pre-clinical receptor research study rimorphin sensor sensory stimulus small molecule therapeutic target

项目摘要

These peptide-based drugs normally exhibit very specific targeting to the desired receptor. However, in order to exert their therapeutic effects, they must also be able to cross into the brain and be enzymatically stable. In this proposal, the transport and metabolism of dynorphin A (Dyn A) at the blood-brain barrier (BBB) is investigated. Dyn A is a natural ligand of the kappa opioid receptor. Analogs of dynorphin and its metabolites have been investigated for the treatment of peripheral pain, drug addiction, and affective disorders. Paradoxically, Dyn A has also been shown to be neurotoxic. Elevated levels of this peptide in the CNS has been associated with neuropathic pain and Alzheimer's disease. Neuropeptides, such as dynorphin, can play multiple roles in vivo including that of a neurotransmitter, neuromodulator, and hormone. In contrast to small molecule neurotransmitters such as glutamate and dopamine, neuropeptides are not taken back up by neurons following their release but are metabolized in the extracellular space into smaller peptide fragments. These fragments can directly affect the cells in the extracellular space in the surrounding area, pass through the BBB, and exert effects at sites far removed from the site of their initial release. There are three main goals of this proposal. The first is to investigate the transport and metabolism of Dyn A 1-17, its metabolites, and synthetic analogs across the BBB. Information acquired through these experiments will lead to a better understanding of the mechanism of transport and will make it possible to produce better therapeutics targeted at the kappa opioid receptor. The second is to develop separationbased sensors that can be used to monitor the effects of dynorphin and its metabolites on neurotransmitter release in the CMS. The third objective is to develop a separation-based sensor that can be placed onanimal so that measurements of neurotransmitters and behavior can be made simultaneously, using awake, freely roaming animals. These techniques will be employed to study the pharmacological actions of Dyn A at the BBB and in the CNS. The methodology developed here will be generally applicable to all neurochemical studies in which the measurement of blood brain barrier transport or neurotransmitters is desired, especially those cases where monitoring behaviour is also of interest. Significance: Dynorphin is an important neuropeptide that is involved in pain, cocaine addiction, depression, and Alzheimer's disease. A better understanding of the transport and metabolism of this peptide across the BBB will assist scientists in producing better treatments for these diseases. The analytical methods developed in this proposal will also be of general utility to scientists involved in CNS research.

这些基于肽的药物通常表现出对所需受体的非常特异性的靶向。但在为了发挥它们的治疗效果，它们还必须能够进入大脑并被酶促消化。稳定强啡肽A（DynA）在血脑屏障（BBB）上的转运和代谢被调查。强啡肽A是κ阿片受体的天然配体。强啡肽类似物及其已经研究了代谢物用于治疗外周疼痛、药物成瘾和情感障碍。紊乱巧合的是，Dyn A也被证明是神经毒性的。这种肽的水平升高， CNS与神经性疼痛和阿尔茨海默病有关。神经肽，如强啡肽，可以在体内发挥多种作用，包括神经递质，神经调节剂和激素。与小分子神经递质如谷氨酸和多巴胺，神经肽在释放后不会被神经元吸收，而是在神经元中代谢。细胞外空间分解成更小的肽片段。这些片段可以直接影响细胞中的细胞，周围区域的细胞外空间，穿过BBB，并在远离的部位发挥作用从它们最初释放的地方这项建议有三个主要目标。第一个是研究的运输和代谢 Dyn A 1-17、其代谢物和合成类似物穿过BBB。通过这些渠道获得的信息实验将导致更好地了解运输机制，并将使人们有可能产生针对κ阿片受体的更好的治疗剂。二是发展分离式可用于监测强啡肽及其代谢物对神经递质的影响的传感器在CMS中释放。第三个目标是开发一种可以放置在动物身上的基于分离的传感器因此，神经递质和行为的测量可以同时进行，使用清醒，自由漫游的动物这些技术将用于研究Dyn A的药理作用， BBB和CNS中。这里开发的方法将普遍适用于所有神经化学需要测量血脑屏障转运或神经递质的研究，特别是在这些情况下，监测行为也很重要。强啡肽是一种重要的神经肽，与疼痛、可卡因成瘾、抑郁症和老年痴呆症更好地了解这种肽的运输和代谢将有助于科学家为这些疾病提供更好的治疗方法。分析本建议中开发的方法也将对参与CNS研究的科学家具有普遍实用性。