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Endogenous Benzodiazepines in the Brain

大脑中的内源性苯二氮卓类药物

基本信息

批准号：
9346120
负责人：
CYNTHIA M CZAJKOWSKI
金额：
$ 22.31万
依托单位：
UNIVERSITY OF WISCONSIN-MADISON
依托单位国家：
美国
项目类别：
财政年份：
2016
资助国家：
美国
起止时间：
2016-09-15 至 2021-08-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/9346120
关键词：
Address Anti-Anxiety Agents Anticonvulsants Anxiety Area Astrocytes Autistic Disorder Basal Ganglia Benzodiazepines Binding Binding Sites Biological Biomedical Research Brain Brain region Cell Nucleus Cells Chemicals Cleaved cell Data Diazepam Diazepam Binding Inhibitor Electrodes Electrophysiology (science)Epilepsy Foundations Fragile X Syndrome Functional disorder GABA Modulators GABA-A Receptor Glutamates Interneurons Ligands Link Mass Spectrum Analysis Measures Mediating Mental disorders Muscle relaxants Names Neurologic Neurons Peptide Fragments Peptides Pharmaceutical Preparations Pharmacology Phosphopeptides Play Process Property Protein Analysis Proteins Recombinants Role Schizophrenia Scientific Inquiry Scientist Signal Transduction Sleeplessness System Testing Thalamic structure Work cell type drug development experimental study gamma-Aminobutyric Acid human disease immunoreactivity induced pluripotent stem cell insight lateral ventricle neurogenesis neuroregulation neurotransmission new therapeutic target receptor sedative subventricular zone voltage clamp

项目摘要

Project Summary Benzodiazepines (BZDs) are widely prescribed drugs and exert their anxiolytic, muscle relaxant, sedative, and anticonvulsant actions by binding to GABA-A receptors (GABARs) and potentiating GABA-induced currents. Since their synthesis over 50 years ago, scientists have searched for endogenous ligands in the brain that bind to the BZD binding site and modulate GABAR activity. Recent evidence suggests a 10 kDa protein named `Diazepam binding inhibitor' (DBI) is the brain's endogenous BZD (endozepine). Depending on the brain region, DBI can potentiate or inhibit GABAR activity suggesting that the brain can modulate GABAR-mediated neuronal inhibition by controlling the levels of DBI and its cleavage products. Little, however, is known about how DBI levels are regulated, how it is processed, or how DBI exerts its positive versus negative effects on GABAR activity. Experiments proposed will address these fundamental questions, which will validate DBI's role as an endogenous BZD and provide new mechanistic insights into how endogenous BZDs regulate GABA- mediated inhibition in the brain. Decreases in GABAergic neurotransmission are linked to numerous neurological and mental health disorders such as insomnia, epilepsy, anxiety, autism, Fragile X and schizophrenia. Whether regional changes in DBI levels or DBI cleavage products contribute to human disease is unknown. Our findings will open up new areas of scientific inquiry and have the potential to reveal new targets for therapeutic drug development.

项目摘要苯二氮卓类（BZD）是广泛使用的处方药，并发挥其抗焦虑、肌肉松弛、镇静和抗炎作用。通过结合GABA-A受体（GABAR）和增强GABA诱导电流的抗惊厥作用。自50多年前合成以来，科学家们一直在寻找大脑中的内源性配体，与BZD结合位点结合并调节GABAR活性。最近的证据表明，一种10 kDa的蛋白质， “地西泮结合抑制剂”（DBI）是脑内的内源性BZD（endozepine）。取决于大脑 DBI可以增强或抑制GABAR活性，表明大脑可以调节GABAR介导的通过控制DBI及其裂解产物的水平来抑制神经元。然而，人们对 DBI水平是如何调节的，它是如何处理的，或者DBI如何对 GABAR活动。提出的实验将解决这些基本问题，这将验证DBI的作用作为内源性BZD，并提供了内源性BZD如何调节GABA的新机制见解- 介导的抑制作用。GABA能神经传递的减少与许多神经和精神健康障碍，如失眠、癫痫、焦虑、自闭症、脆性X染色体和精神分裂症DBI水平或DBI裂解产物的区域变化是否有助于人类疾病不明我们的发现将开辟科学探索的新领域，并有可能揭示新的治疗药物开发的目标。