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.

项目摘要 药理学是研究药物如何产生预期的治疗结果的学科。就像药物一样 经过开发，它们被设计成针对体内的特定受体，并改变细胞的功能方式。的 这些药物靶点，G蛋白偶联受体(GPCRs)是最常见的，我的研究检查了 一旦药物与GPCRs结合，GPCRs如何发挥作用。GPCRs通过启动G蛋白信号来改变细胞反应。 这种信号被认为只发生在细胞表面，但新的研究表明，G蛋白 信号也发生在细胞内。因此，重要的是要了解GPCR是如何来往的 亚蜂窝位置会影响它们的整体信令能力。大麻素受体-1(CB1)是一种gpr。 在整个大脑中大量表达。它具有多种神经生物学作用，已成为一种潜在的药物。 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，会产生各种各样的意外副作用。例如，THC，精神活性物质 大麻的一种成分，是一种大麻素，与药物使用和药物滥用障碍密切相关。 我的研究重点是了解与CB1结合的大麻素是如何产生不同的 生物学结果。我的目标是通过研究大麻类物质如何使其成为有希望的治疗靶点 调节CB1‘S的亚细胞活性。了解细胞内gpr信号的功能作用是一种新的 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。这可能对理解变化具有重要意义 CB1激活的结果，因为与GPCRs相比，CB1显示出显著的亚细胞定位 是最常被研究的。然而，Cb1‘S亚细胞定位的意义还需要进一步的研究 调查。拟议的研究项目将调查CB1是如何被大麻类化合物差异激活的。 在大脑内部，同时描绘CB1激活的空间成分。取得了良好的效果 该项目的完成将为开发CB1作为可行的治疗靶点提供一个框架。