The Ionotropic Cannabinoid Receptor TRPV1

离子型大麻素受体 TRPV1

基本信息

批准号：
10385705
负责人：
Chanté Muller
金额：
$ 0.95万
依托单位：
UNIVERSITY OF NORTH CAROLINA GREENSBORO
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：
2021-07-01 至 2022-08-09
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10385705
关键词：
Absence of pain sensation Action Potentials Affect Agonist Allosteric Site Alzheimer&apos s Disease American Analgesics Applications Grants Award Binding Binding Sites Biological Assay Brain CNR1 gene CNR2 gene Calcium Cannabinoids Cannabis Cannabis sativa plant Cells Coin Collaborations Complex Computational Technique Cryoelectron Microscopy Data Detection Development Docking Drug Design Endocannabinoids Environment Epilepsy Etiology Event Fellowship G-Protein-Coupled Receptors Goals Human Hydration status Image Investigation Ion Channel Ions Lead Learning Ligand Binding Ligands Lipid Bilayers Location Malignant Neoplasms Memory Modeling Molecular Conformation Mutagenesis Mutation Nociception Opioid Pain Pain management Pathway interactions Peripheral Nervous System Persons Plants Postdoctoral Fellow Process Property Publishing Rattus Refractory Research Personnel Risk Scientist Series Stimulus Structure Symptoms Syndrome System TRP channel TRPV channel TRPV1 gene Testing Therapeutic Time Training Universities Vanilloid Work anandamide antagonist appetite loss cannabinoid receptor capsaicin receptor chronic pain chronic pain management chronic painful condition combat computer studies conformer desensitization experience experimental study field study interest knowledge base molecular dynamics pain perception pain relief pain sensation painful neuropathy programs rational design receptor side effect simulation supercomputer three-dimensional modeling

项目摘要

PROJECT SUMMARY Chronic pain encompasses a wide range of symptoms and pathways, making the condition notoriously difficult to treat. While opioid treatments can be effective, the unwanted side effects and risk of abuse warrant the investigation of safer treatment options. Cannabis sativa has been utilized for millennia for its medicinal properties and has been studied for its therapeutic potential in the treatment of epilepsy, Alzheimer’s disease, appetite loss, and pain. While most people think of the canonical CB1/CB2 receptors when it comes to cannabinoids, other GPCRs and TRP channels can be modulated by a subset of these ligands. In fact, this project focuses on one of the TRP channels that has been coined an “ionotropic cannabinoid receptor,” TRPV1. TRPV1 (also known as the capsaicin receptor) is a homotetrameric, polymodal channel, and is located in the peripheral nervous system and has been implicated in the perception of pain. This project seeks to understand how and where various cannabinoid ligands bind to and activate TRPV1, in order to aid in rational drug design. The mechanism by which TRPV1 relieves pain is paradoxical; upon activation of TRPV1, ions (preferentially calcium) enter the cell and cause a series of calcium-dependent processes. This generates an action potential which is then propagated to the brain, resulting in the sensation of pain. Shortly after activation, TRPV1 is desensitized, rendering it refractory to any further stimulation, resulting in the paradoxical analgesic effect. Because of this, targeting TRPV1, an ion channel that contributes to the detection of painful stimuli, may be an effective approach in treating chronic pain syndromes. By utilizing computational techniques such as modeling and molecular dynamics simulations, interactions of cannabinoid ligands can be observed with TRPV1, which provide atomic level descriptions that are unavailable to experimental studies. Preliminary data suggests that anandamide may bind to TRPV1 in an allosteric site apart from the location of vanilloid binding. To further investigate this result, a grant application to use the supercomputer ANTON2 was written and awarded, and ~10μs of additional data was gathered thus far. Since this work is part of a combined computational/experimental effort that centers on identifying relevant residues for binding and modes of TRPV1 activation/inactivation by cannabinoid ligands, the results from these simulations will be tested via mutagenesis and functional experimental studies by working in the lab of Dr. Mary Abood at Temple University and collaborating with Dr. Eugen Brailoiu for live cell calcium imaging.

项目概要慢性疼痛包含多种症状和途径，使病情变得非常困难虽然阿片类药物治疗可能有效，但不良副作用和滥用风险值得采取。对更安全的治疗方案的研究大麻因其药用已有数千年的历史。特性，并已研究其在治疗癫痫、阿尔茨海默病、食欲减退和疼痛，而大多数人一提到经典的 CB1/CB2 受体。事实上，大麻素、其他 GPCR 和 TRP 通道可以通过这些配体的子集进行调节。该项目的重点是 TRP 通道之一，该通道被称为“离子型大麻素受体”TRPV1。 TRPV1（也称为辣椒素受体）是同源四聚体、多模式通道，位于该项目旨在了解周围神经系统并与疼痛感知有关。各种大麻素配体如何以及在何处结合并激活 TRPV1，以帮助合理的药物设计。 TRPV1 缓解疼痛的机制在 TRPV1、离子（优先）激活时是矛盾的；钙）进入细胞并引起一系列钙依赖性过程。 TRPV1 被激活后不久就会传播到大脑，从而产生疼痛感。脱敏，使其难以接受任何进一步的刺激，从而产生矛盾的镇痛效果。因此，针对 TRPV1（一种有助于检测疼痛刺激的离子通道）可能是一种有效的方法。治疗慢性疼痛综合征的有效方法。通过建模和分子动力学模拟等计算利用技术，可以使用 TRPV1 观察大麻素配体，它提供了无法获得的原子级描述实验研究表明 anandamide 可能与 TRPV1 的变构位点结合。除了香草酸结合的位置之外，为了进一步研究这一结果，一项拨款申请使用了超级计算机 ANTON2 已编写并授予，迄今为止已收集了大约 10μs 的额外数据。这项工作是综合计算/实验工作的一部分，其重点是确定相关残基大麻素配体的结合和 TRPV1 激活/失活模式，这些模拟的结果将在 Mary Abood 博士的实验室工作，通过诱变和功能实验研究进行测试天普大学与 Eugen Brailoiu 博士合作进行活细胞钙成像。