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.

项目摘要 慢性疼痛会影响超过5000万人的经济负担。目前，有 除了基于阿片类药物的药物和非甾体类抗炎药物以外，很少有有效的治疗方法。其中许多 治疗具有很高的滥用和/或副作用的潜力。有必要发现和研究小说 治疗急性和慢性疼痛的生物学靶标。该提议着重于一个旧的分子靶标， Sigma 2/跨膜蛋白97（σ2/TMEM97）接收器，仅在最后五个中与疼痛有关 年。 σ2/TMEM97受体是内质网和质膜跨膜蛋白 在胆固醇代谢和钙稳态中具有已知作用。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标，并证明 σ2/TMEM97选择配体能够逆转神经性损伤诱导的机械性超敏反应 老鼠。这种作用的细胞机制或效应的解剖位置都不是 确定。实际上，在σ2/tmem97和 其配体的药理特性已成为准确解释药理行为的障碍 效果。为了推进先前对σ2/TMEM97作为疼痛治疗的治疗靶点的研究，我的目标是 研究σ2/TMEM97在行为，细胞和细胞上的伤害感受的程度 分子水平。我将通过使用转基因动物检查差异来研究σ2/TMEM97的作用 在外周神经系统中σ2/TMEM97驱动的伤害感受的细胞活性和分子谱图 （PNS）。该提案的目的是1）了解σ2/TMEM97-的细胞和分子特征 相关的慢性炎症性疼痛中的行为伤害感受和2）确定伤害感受器特异性的 σ2/TMEM97功能的丢失导致与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测序数据的大量培训机会 分析为神经科学和生物医学领域独立职业准备PI。