Feedback regulation of cannabinoid receptor trafficking and signaling

大麻素受体运输和信号传导的反馈调节

• 批准号: 10312886
• 负责人: Joshua Lott
• 金额: $ 1.71万
• 依托单位: UNIVERSITY OF MICHIGAN AT ANN ARBOR
• 依托单位国家: 美国
• 财政年份: 2022
• 资助国家: 美国
• 起止时间: 2022-02-01 至 2022-04-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10312886
• 关键词: Address; Affect; Agonist; Alternative Splicing; Anxiety; Area; Binding; Biological; Biology; Biosensor; Brain; CNR1 gene; Cannabinoids; Cannabis; Cell physiology; Cell surface; Cells; Cellular biology; Clinical; Coupled; Desire for food; Disease; Drug Targeting; Drug usage; Epilepsy; Exhibits; Family; Feedback; Foundations; Future; G Protein-Coupled Receptor Signaling; G-Protein Signaling Pathway; G-Protein-Coupled Receptors; GTP-Binding Protein alpha Subunits, Gs; GTP-Binding Proteins; Genetic; Image; Intracellular Membranes; Investigation; Knowledge; Learning; Ligands; Location; Medicine; Mental Depression; Methods; Modeling; Molecular Conformation; Neuraxis; Neurobiology; Neurologic; Neuropharmacology; Outcome; Pain; Permeability; Pharmaceutical Preparations; Pharmacology; Physiological; Play; Protein Isoforms; Proteins; Receptor Activation; Regulation; Research; Research Project Grants; Resolution; Role; Signal Pathway; Signal Transduction; Signaling Protein; Site; Stimulus; Substance abuse problem; Surface; Testing; Therapeutic; Therapeutic Agents; Therapeutic Human Experimentation; Training; Translating; Variant; Work; base; cannabinoid receptor; design; experimental study; extracellular; fluorescence imaging; innovation; member; novel; pleiotropism; receptor; receptor function; response; side effect; skills; therapeutic target; therapy outcome; trafficking

Project Summary Pharmacology is the study of how medicine works to produce a desired therapeutic outcome. As medicines are developed, they are designed to target specific receptors within the body and alter the way cells function. Of these drug targets, G-protein coupled receptors (GPCRs) are the most common, and my research examines how GPCRs function once drugs bind to them. GPCRs alter cellular responses by initiating G-protein signaling. This signaling was thought to occur only at the surface of cells, but emerging research has shown that G-protein signaling occurs within the cell as well. Therefore, it is important to understand how GPCR trafficking to and from subcellular locations impact their overall signaling capabilities. The cannabinoid receptor-1 (CB1) is a GPCR heavily expressed throughout the brain. It plays numerous neurobiological roles and has been a potential drug target in managing appetite, depression, pain and anxiety. However, drugs that bind to CB1, also known as cannabinoids, produce a wide variety of unintended side effects. For example, THC, the psychoactive component of cannabis, is a cannabinoid that is heavily associated with drug use and substance abuse disorders. My research is particularly focused on understanding how cannabinoids that bind to CB1 produce different biological outcomes. I aim to expand their value as promising therapeutic targets by studying how cannabinoids regulate CB1's subcellular activity. Understanding the functional roles of intracellular GPCR signaling is a new and exciting area of pharmacology and therapeutic research where drugs can be specifically designed for intracellular targeting of receptors. This could have significant implications for understanding the varying outcomes of CB1 activation, as CB1 exhibits significant subcellular localization when compared to GPCRs that are most commonly studied. However, the significance of CB1's subcellular localization requires further investigation. The proposed research project will investigate how CB1 is differentially activated by cannabinoids within the brain, while simultaneously delineating the spatial components of CB1 activation. The results gained from completion of this project will provide a framework for developing CB1 as a viable therapeutic target.

项目概要 药理学是研究药物如何发挥作用以产生所需治疗结果的学科。正如药物一样 它们的开发旨在针对体内的特定受体并改变细胞的功能方式。的 在这些药物靶标中，G 蛋白偶联受体 (GPCR) 是最常见的，我的研究表明 药物与 GPCR 结合后如何发挥作用。 GPCR 通过启动 G 蛋白信号传导来改变细胞反应。 人们认为这种信号传导仅发生在细胞表面，但新兴研究表明 G 蛋白 信号传导也发生在细胞内。因此，了解 GPCR 如何贩运至和来自 亚细胞位置影响其整体信号传导能力。大麻素受体 1 (CB1) 是一种 GPCR 在整个大脑中大量表达。它具有多种神经生物学作用，并且是一种潜在的药物 控制食欲、抑郁、疼痛和焦虑的目标。然而，与 CB1 结合的药物，也称为 大麻素会产生多种意想不到的副作用。例如，THC，一种精神活性物质 大麻的成分，是一种与吸毒和药物滥用疾病密切相关的大麻素。 我的研究特别侧重于了解与 CB1 结合的大麻素如何产生不同的 生物学结果。我的目标是通过研究大麻素如何扩大其作为有希望的治疗靶点的价值 调节CB1的亚细胞活性。了解细胞内 GPCR 信号传导的功能作用是一个新的课题 以及令人兴奋的药理学和治疗研究领域，药物可以专门设计用于 受体的细胞内靶向。这可能对理解不同的 CB1 激活的结果，因为与 GPCR 相比，CB1 表现出显着的亚细胞定位 最常被研究。然而，CB1亚细胞定位的意义还需要进一步研究。 调查。拟议的研究项目将研究大麻素如何差异激活 CB1 在大脑内，同时描绘 CB1 激活的空间成分。取得的成果 该项目完成后将为将 CB1 开发为可行的治疗靶点提供一个框架。