Harnessing acid-sensing ion channel toxins for therapeutic purposes

利用酸敏感离子通道毒素进行治疗

基本信息

批准号：
10322747
负责人：
David Malcom MacLean
金额：
$ 19.25万
依托单位：
UNIVERSITY OF ROCHESTER
依托单位国家：
美国
项目类别：
财政年份：
2021
资助国家：
美国
起止时间：
2021-01-01 至 2023-06-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10322747
关键词：
ASIC channel Acidity Acidosis Address Affinity Amino Acids Amygdaloid structure Anti-Anxiety Agents Antidepressive Agents Anxiety Anxiety Disorders Attenuated Bathing Benzodiazepines Binding Binding Sites Biological Assay Blood Blood - brain barrier anatomy Brain C-terminal Carbon Dioxide Cells Cerebrospinal Fluid Chemicals Data Disease Docking Drug Screening Drug Targeting Electrophysiology (science)Family Foundations Freezing Fright Funding Generalized Anxiety Disorder Genes Genetic Healthcare Homology Modeling Human Hypersensitivity Hyperventilation Inhalation Ion Channel Knock-out Lateral Lead Liquid substance Lobe Long-Term Potentiation Maps Measures Modeling Molecular Mus Mutate N-terminal Nervous system structure Neuraxis Neurons Panic Attack Panic Disorder Patients Peptides Pharmaceutical Preparations Pharmacological Treatment Pharmacology Phenotype Publishing Reader Reporting Resolution Rodent Role Sequence Analysis Shock Site Snakes Social Impacts Specific qualifier value Spiders Structural Models Structure Synapses Testing Therapeutic Toxin Western Blotting Work abuse liability crosslink drug development economic impact experimental study foot high throughput screening innovation insight molecular modeling new therapeutic target novel novel therapeutics patch clamp pharmacophore programs receptor side effect small molecule treatment of anxiety disorders virtual

项目摘要

PROJECT SUMMARY/ABSTRACT Generalized anxiety and panic disorder are debilitating disorders resulting in severe social and economic impact for patients. Antidepressants and benzodiazepines are the current frontline pharmacological treatments but both medication types come with undesirable side effects, well- documented compliance issues and/or abuse potential. Acid-sensing ion channels (ASICs) represent a new drug target and potential treatment avenue for these conditions. ASICs are a family of pH- activated ion channels found throughout the nervous system, being especially enriched in the amygdala. Genetic deletion of ASIC genes in mice results in several anxiolytic phenotypes including greater exploration in open field maze experiments, attenuated freezing in tone-foot shock pairing and the complete loss of long-term potentiation between synapses in the lateral amygdala. Pharmacological inhibition of ASICs using the highly selective psalmotoxin1 peptide also produces anxiolytic effects when injected into rodents. Unfortunately, psalmotoxin1 does not readily cross the blood-brain barrier and there are currently no high affinity/high selectivity small molecule ASIC drugs. Here we propose to furnish novel drugs leads using newly described ASIC selective toxins. To do this we will first combine electrophysiology and high throughput assays to map interactions between human ASIC1a and a selective toxin. Subsequently, we will use molecular modelling to predict hASIC1a-toxin binding sites. Finally, we will test these proposed binding sites using electrophysiology and chemical crosslinking. Together, these aims will identify the binding sites and mechanism of action of high affinity ASIC selective toxins, providing foundational insight into the channel while expanding the therapeutic armamentarium. Given the involvement of ASICs in anxiety disorders, and a myriad of other conditions, such pharmacological advances could have broad health care implications.

项目摘要/摘要普遍的焦虑和恐慌症正在使人衰弱，导致严重的社会和对患者的经济影响。抗抑郁药和苯二氮卓类是当前的前线药理学治疗但两种药物类型都具有不良的副作用，记录了合规性问题和/或滥用潜力。酸性离子通道（ASIC）代表针对这些条件的新药物目标和潜在的治疗途径。 ASIC是一个pH的家族在整个神经系统中发现的激活离子通道，特别丰富杏仁核。小鼠ASIC基因的遗传缺失导致几种抗焦虑表型，包括在开放田迷宫实验中进行了更大的探索，在音调脚冲击配对中减弱了冻结侧杏仁核突触之间的长期增强完全损失。药理使用高选择性psalmotoxin1肽对ASIC的抑制也会产生抗焦虑作用注入啮齿动物时。不幸的是，psalmotoxin1不容易越过血脑屏障目前没有高亲和力/高选择性小分子ASIC药物。在这里我们建议提供新的药物使用新描述的ASIC选择性毒素引导。为此，我们首先将电生理学和高吞吐量测定，以绘制人ASIC1A与A之间的相互作用选择性毒素。随后，我们将使用分子建模来预测hasic1a毒素结合位点。最后，我们将使用电生理学和化学交联测试这些提出的结合位点。这些目的共同确定了高亲和力ASIC的结合位点和作用机理选择性毒素，在扩展治疗性的同时为渠道提供基本洞察力武术。鉴于ASIC参与焦虑症和无数其他疾病，这种药理进步可能具有广泛的医疗保健意义。