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药物（BZD）是广泛处方的药物，并施加抗焦虑，肌肉松弛剂，镇静剂和通过与GABA-A受体（GABAR）结合并增强GABA诱导的电流来抗惊厥作用。自从50年前的合成以来，科学家就搜索了大脑中的内源配体到BZD结合位点并调节Gabar活性。最近的证据表明一种10 kDa蛋白 “地西爱结合抑制剂”（DBI）是大脑的内源性BZD（resozepine）。取决于大脑区域，DBI可以增强或抑制GABAR活性，这表明大脑可以调节Gabar介导的神经元抑制通过控制DBI及其裂解产物的水平。但是，很少知道如何调节DBI水平，如何处理或DBI如何对其正面和负面影响施加 Gabar活动。提出的实验将解决这些基本问题，这将验证DBI的角色作为内源性BZD，并提供了有关内源性BZD如何调节GABA-的新机械见解介导的大脑抑制作用。 GABA能神经传递的降低与许多神经和心理健康障碍，例如失眠，癫痫，焦虑，自闭症，脆弱的X和精神分裂症。 DBI水平的区域变化还是DBI裂解产品有助于人类疾病是未知的。我们的发现将为科学询问的新领域开放，并有可能揭示新的新领域治疗药物开发的靶标。