Initial Development of AEG-1 inactivation as a possible strategy for pain treatment

初步开发 AEG-1 失活作为疼痛治疗的可能策略

基本信息

批准号：
10454012
负责人：
M. Imad Damaj
金额：
$ 117.97万
依托单位：
VIRGINIA COMMONWEALTH UNIVERSITY
依托单位国家：
美国
项目类别：
财政年份：
2022
资助国家：
美国
起止时间：
2022-05-01 至 2024-04-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10454012
关键词：
Address Affect Analgesics Animals Astrocytes Behavior Behavioral Biological Cells Chemotherapy-induced peripheral neuropathy Chronic Chronic inflammatory pain Clinic Clinical Trials Complex Development Disease Female Freund&apos s Adjuvant Gene Expression Genes Inflammation Inflammatory Knockout Mice Knowledge Lipopolysaccharides Macrophage Activation Measures Mechanics Mediating Medical Microglia Migraine Modality Modeling Molecular Motor Activity Mus Myeloid Cells NF-kappa B NFKB Signaling Pathway Nociception Nociceptive Reflex Non-Malignant Opioid Output Pain Pain management Play Proteins RNA Interference Reflex action Regulation Role Running Scaffolding Protein Signal Transduction Small Interfering RNA Testing Tissues allodynia chronic neuropathic pain chronic pain constriction cytokine design efficacy evaluation genome wide association study human study knock-down macrophage male mouse model nanoparticle nanoparticle delivery non-opioid analgesic novel opioid epidemic pain behavior pain model pain relief protein function protein protein interaction response spontaneous pain transcription factor

项目摘要

Summary Adequate management of pain is an unmet medical need. Opioids remain an important class of pain medications but their use in chronic, non-malignant pain has contributed to what is now referred to as the “opioid epidemic”. There is clearly an urgent need to identify and validate novel targets allowing development of novel non-opioid analgesics that are effective and safe. This proposal focuses on a new molecule, Astrocyte elevated gene-1 (AEG-1), as a possible target for pain. AEG-1, also known as metadherin (MTDH), is a scaffold protein which mediates its function by protein-protein interaction. AEG-1 functions as a scaffold protein in multiple intermediary signaling complexes in NF-kB signaling pathway, thereby functioning as a fundamental molecule in NF-kB activation. NF-kB is a key transcription factor regulating pro-inflammatory cytokines and AEG-1 is a major regulator of inflammation. AEG-1 KO mice show a profound inhibition of inflammation and AEG-1 KO macrophages show profound inhibition of lipopolysaccharide (LPS)-induced NF-kB activity and inflammatory gene expression. NF-kB plays a major regulatory role in chronic inflammatory pain. Since AEG-1 regulates NF-kB it may be hypothesized that AEG-1 might function as a key molecule regulating pain mechanisms. Our preliminary studies demonstrate that nociceptive behaviors and inflammation in both the complete Freund adjuvant (CFA) chronic inflammatory pain were significantly reduced in AEG-1 KO mice compared to AEG-1 WT mice, without affecting motor activity and coordination of the animals. These findings identify a key role of AEG-1 in regulating chronic pain and a potential target for ameliorating chronic pain. We hypothesize that AEG-1 is a valid target regulating pain behaviors and AEG-1 inhibition might be developed as a potential strategy for developing new analgesics for chronic pain. We will test our hypothesis in Aim 1 by analyzing pain behaviors in two chronic neuropathic pain models in AEG-1 KO and WT mice. Aim 2 will investigate the role of macrophage/microglia AEG-1 cells by using myeloid cell-specific conditional AEG-1 KO mouse. In Aim 3 we will evaluate efficacy of macrophage-targeted nanoparticles delivering AEG-1 siRNA to ameliorate chronic inflammatory pain. Our studies will identify AEG- 1 as a novel and crucial regulatory molecule modulating pain response and will pave the way for developing RNAi strategy for pain. Multiple clinical trials are ongoing to test siRNAs targeting diverse genes in a variety of diseases thereby establishing potential application of this strategy to manage pain in the clinics.

概括充分治疗疼痛是一项未得到满足的医疗需求，阿片类药物仍然是一类重要的疼痛。药物治疗，但它们在慢性非恶性疼痛中的使用导致了现在所谓的“疼痛” “阿片类药物流行病”。显然迫切需要确定和验证允许开发的目标。有效且安全的新型非阿片类镇痛药该提案重点关注一种新分子，星形胶质细胞升高基因 1 (AEG-1)，作为疼痛的可能靶标，也称为麦粘蛋白 (MTDH)，是一种支架蛋白，通过蛋白质-蛋白质相互作用介导其功能。 NF-kB 信号通路中多个中间信号复合物中的蛋白质，从而充当 NF-kB 激活的基本分子 NF-kB 是调节促炎症的关键转录因子。细胞因子和AEG-1是炎症的主要调节因子，AEG-1 KO小鼠表现出深刻的抑制作用。炎症和 AEG-1 KO 巨噬细胞对脂多糖 (LPS) 诱导的炎症具有显着抑制作用 NF-kB 活性和炎症基因表达在慢性疾病中起着重要的调节作用。由于 AEG-1 调节 NF-kB，因此 AEG-1 可能发挥关键作用。我们的初步研究表明伤害性行为和炎症在弗氏完全佐剂（CFA）慢性炎症疼痛中均显着与 AEG-1 WT 小鼠相比，AEG-1 KO 小鼠的基因表达减少，但不影响运动活动和协调性这些发现确定了 AEG-1 在调节慢性疼痛中的关键作用和潜在目标。我们勇敢地承认 AEG-1 是调节疼痛行为的有效靶标。 AEG-1 抑制可能被开发为开发新的慢性疼痛镇痛药的潜在策略。我们将通过分析两种慢性神经病理性疼痛模型的疼痛行为来检验我们在目标 1 中的假设。 AEG-1 KO 和 WT 小鼠 Aim 2 将使用 AEG-1 细胞研究巨噬细胞/小胶质细胞的作用。骨髓细胞特异性条件 AEG-1 KO 小鼠在目标 3 中，我们将评估巨噬细胞靶向的功效。纳米颗粒递送 AEG-1 siRNA 以改善慢性炎症疼痛我们的研究将鉴定 AEG-。 1 作为一种新颖且重要的调节疼痛反应的调节分子，将为开发铺平道路针对疼痛的 RNAi 策略正在进行中，以测试针对多种基因的 siRNA。从而确定该策略在临床上管理疼痛的潜在应用。