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

项目总结 慢性疼痛影响着5000多万人，带来巨大的经济负担。目前，有以下几种 除了阿片类药物和非类固醇抗炎药物外，几乎没有其他有效的治疗方法。其中许多 治疗有很高的滥用和/或副作用的可能性。发现和研究小说是必要的 治疗急性和慢性疼痛的生物靶点。这项提议关注的是一个古老的分子靶标， Sigma 2/跨膜蛋白97(σ2/TMEM97)受体，只有在过去的五年中才与疼痛有关 好几年了。σ-2/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有已知的影响。行为药理学最新研究进展 研究了σ2/TMEM97作为治疗疼痛的潜在靶点，并证明了 σ-2/TMEM97选择性配体逆转神经病理性损伤诱导的机械超敏反应 老鼠。无论是这种效应的细胞机制，还是这种效应的解剖位置，目前都还不清楚。 已确认身份。事实上，在疼痛的背景下，对σ2/TMEM97细胞特性的有限了解和 其配体的药理性质一直是准确解释药理行为的障碍 效果。为了推进σ2/TMEM97作为疼痛治疗靶点的先前研究，我的目标是 研究σ2/TMEM97在行为、细胞和 分子水平。我将利用转基因动物来研究σ2/TMEM97的作用 外周神经系统中σ-2/TMEM97介导的伤害性感受的细胞活性和分子特征 (PNS)。这项建议的目标是1)了解σ2/TMEM97的细胞和分子特征- 慢性炎症性疼痛的相关行为伤害性感觉和2)确定伤害性感受器特异性 σ2/TMEM97功能缺失导致与三叉神经节扰动相关的行为改变。这个项目 包括在分子生物学、动物行为和RNA测序数据方面的重要培训机会 分析为PI在神经科学和生物医学领域的独立职业生涯做准备。

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.