Sigma 2 Receptor (TMEM97): Investigating the Peripheral Role of this Novel Therapeutic Target for Pain

Sigma 2 受体 (TMEM97)：研究这种新型疼痛治疗靶点的外周作用

• 批准号: 10607436
• 负责人: Veronica Minsu Hong
• 金额: $ 4.34万
• 依托单位: UNIVERSITY OF TEXAS DALLAS
• 依托单位国家: 美国
• 财政年份: 2023
• 资助国家: 美国
• 起止时间: 2023-02-01 至 2025-11-30
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10607436
• 关键词: Acute Pain; Affect; Affinity Chromatography; Agonist; Anatomy; Animal Behavior; Behavior; Behavioral; Biological; Biological Process; Calcium; Calcium Signaling; Cell membrane; Cell physiology; Cells; Cholesterol Homeostasis; Chronic inflammatory pain; Clinic; Crossbreeding; Data; Data Analyses; Down-Regulation; Economic Burden; Endoplasmic Reticulum; Experimental Designs; Future; Gene Expression; Genes; Genetic Transcription; Genomic approach; Goals; Homeostasis; Human; Hypersensitivity; In Situ Hybridization; In Vitro; Individual; Inflammation; Inflammatory; Injury; Integral Membrane Protein; Interleukin-6; Investigation; Knock-out; Knockout Mice; Knowledge; Learning; Ligands; Link; Literature; Location; LoxP-flanked allele; Mechanics; Mediating; Molecular; Molecular Biology; Molecular Profiling; Molecular Target; Mus; Neurons; Neuropathy; Neurosciences; Nociception; Nociceptors; Non-Steroidal Anti-Inflammatory Agents; Opioid; Pain; Pain management; Peripheral; Peripheral Nervous System; Pharmaceutical Preparations; Pharmacology; Pharmacology Study; Play; Population; Property; Public Health; Publications; Recovery; Ribosomes; Rodent; Role; Signal Transduction; Site; Spinal Ganglia; System; Techniques; Testing; Therapeutic; Training; Transgenic Animals; Transgenic Mice; Transgenic Organisms; Translating; Up-Regulation; Wild Type Mouse; abuse liability; antagonist; behavioral pharmacology; career; cell type; chronic pain; clinical translation; differential expression; effective therapy; efficacy evaluation; experimental study; ganglion cell; in vivo; induced pluripotent stem cell; inflammatory modulation; inflammatory pain; insight; interdisciplinary approach; loss of function; multi-electrode arrays; neuroregulation; new therapeutic target; novel; pain model; pharmacologic; receptor; response; side effect; sigma-2 receptor; therapeutic target; training opportunity; transcriptome sequencing; transcriptomic profiling

PROJECT SUMMARY Chronic pain affects greater than 50 million individuals with a huge economic burden. Currently, there are few effective treatments other than opioid-based drugs and non-steroidal anti-inflammatory drugs. Many of these treatments have a high potential for abuse and/or side effects. It is necessary to discover and study novel biological targets for the treatment of acute and chronic pain. This proposal focuses on an old molecular target, the Sigma 2/transmembrane protein 97 (σ2/TMEM97) receptor, that has been linked to pain only in the last five years. The σ2/TMEM97 receptor is an endoplasmic reticulum and plasma membrane transmembrane protein with known effects in cholesterol metabolism and calcium homeostasis. Recent behavioral pharmacology studies investigated σ2/TMEM97 as a potential therapeutic target for the treatment of pain and demonstrated that σ2/TMEM97-selective ligands were able to reverse neuropathic injury-induced mechanical hypersensitivity in mice. Neither the cellular mechanisms of this effect nor the anatomical location of the effects have been identified. In fact, limited knowledge in the context of pain of the cellular properties of σ2/TMEM97 and pharmacological properties of its ligands has been a barrier to accurately interpreting pharmacological behavioral effects. To advance the previous studies on σ2/TMEM97 as a therapeutic target for pain treatment, I aim to investigate the extent to which σ2/TMEM97 plays in the processing of nociception at the behavioral, cellular, and molecular level. I will investigate the role of σ2/TMEM97 by utilizing transgenic animals to examine the difference in cellular activity and the molecular profile of σ2/TMEM97-driven nociception in the peripheral nervous system (PNS). The goal of this proposal is to 1) understand the cellular and molecular signature of σ2/TMEM97- associated behavioral nociception in chronic inflammatory pain and 2) determine whether nociceptor-specific loss of σ2/TMEM97 function results in behavioral changes associated with perturbation to the PNS. This project includes significant training opportunities in molecular biology, animal behavior, and RNA sequencing data analysis preparing the PI for an independent career in neuroscience and biomedicine.

项目概要 慢性疼痛影响着超过 5000 万人，带来了巨大的经济负担。目前，有 除阿片类药物和非甾体抗炎药外，几乎没有有效的治疗方法。其中许多 治疗很可能会被滥用和/或产生副作用。需要发现和研究新奇的东西 治疗急性和慢性疼痛的生物靶标。该提案重点关注一个旧的分子靶标， Sigma 2/跨膜蛋白 97 (σ2/TMEM97) 受体，仅在过去五年中才与疼痛相关 年。 σ2/TMEM97 受体是一种内质网和质膜跨膜蛋白 对胆固醇代谢和钙稳态具有已知的影响。最近的行为药理学研究 研究了 σ2/TMEM97 作为治疗疼痛的潜在治疗靶点，并证明 σ2/TMEM97 选择性配体能够逆转神经性损伤引起的机械超敏反应 老鼠。这种效应的细胞机制和效应的解剖学位置都尚未被证实。 确定。事实上，对于 σ2/TMEM97 的细胞特性和疼痛的了解有限。 其配体的药理学特性一直是准确解释药理学行为的障碍 影响。为了推进之前关于 σ2/TMEM97 作为疼痛治疗靶点的研究，我的目标是 研究 σ2/TMEM97 在行为、细胞和行为方面的伤害感受处理中发挥的作用程度 分子水平。我将通过利用转基因动物来检查差异来研究σ2/TMEM97的作用 周围神经系统中细胞活动和 σ2/TMEM97 驱动的伤害感受的分子特征 （PNS）。该提案的目标是 1) 了解 σ2/TMEM97- 的细胞和分子特征 慢性炎症疼痛中相关的行为伤害感受，2) 确定伤害感受器是否具有特异性 σ2/TMEM97 功能丧失会导致与 PNS 扰动相关的行为变化。这个项目 包括分子生物学、动物行为和 RNA 测序数据方面的重要培训机会 分析为 PI 从事神经科学和生物医学的独立职业做好准备。