Multiplex epigenome editing of ion channel expression in nociceptive neurons abolished degenerative IVD-conditioned media-induced mechanical sensitivity.
Multiplex epigenome editing of ion channel expression in nociceptive neurons abolished degenerative IVD-conditioned media-induced mechanical sensitivity.
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DOI：
10.1002/jsp2.1253
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发表时间：
2023-06
期刊：
影响因子：
3.7
通讯作者：
Bowles, Robby D.
中科院分区：
文献类型：
--
作者：
Stover, Joshua D.;Trone, Matthew A.;Lawrence, Brandon;Bowles, Robby D.
下背痛是全球残疾的主要原因，并产生巨大的社会经济影响。已假设退行性椎间盘（IVD）通过使支配椎间盘的伤害性神经元对健康患者中无疼痛的刺激敏感而导致椎间盘源性疼痛。以前，我们证明了退行性IVD使神经元对机械刺激敏感的能力;然而，需要阐明退行性IVD椎间盘源性疼痛机制，以开发直接针对这些机制的治疗策略。在这项研究中，我们利用伤害性神经元的CRISPR表观基因组编辑来确定退行性IVD诱导的机械伤害感受变化的机制，并证明了伤害性神经元的多重CRISPR表观基因组编辑调节炎症诱导的机械伤害感受的能力。利用体外模型，我们证明了退行性IVD产生的IL-6诱导的伤害感受神经元活性增加，以响应机械刺激，由TRPA 1，ASIC 3和Piezo 2离子通道活性介导。一旦这些离子通道被鉴定为退行性IVD诱导的机械伤害感受的介质，我们开发了单一和多重CRISPR表观基因组编辑载体，通过靶向基因启动子组蛋白甲基化调节TRPA 1，ASIC 3和Piezo 2的内源性表达。当递送到伤害感受神经元时，多重CRISPR表观基因组编辑载体消除了退行性IVD诱导的机械伤害感受，同时保留了非病理性神经元活性。这项工作证明了多重CRISPR表观基因组编辑作为一种高度靶向的基于基因的神经调节策略的潜力，特别是用于治疗椎间盘源性疼痛;更广泛地用于治疗炎性慢性疼痛。伤害性神经元中离子通道表达的多重CRISPR表观基因组编辑在椎间盘源性背痛的体外模型中消除了退行性IVD诱导的机械伤害性感受。这些结果证明了伤害感受神经元的多重表观基因组编辑作为椎间盘源性背痛和其他慢性疼痛病症的潜在神经调节策略。
Low back pain is a major contributor to disability worldwide and generates a tremendous socioeconomic impact. The degenerative intervertebral disc (IVD) has been hypothesized to contribute to discogenic pain by sensitizing nociceptive neurons innervating the disc to stimuli that is nonpainful in healthy patients. Previously, we demonstrated the ability of degenerative IVDs to sensitize neurons to mechanical stimuli; however, elucidation of degenerative IVDs discogenic pain mechanisms is required to develop therapeutic strategies that directly target these mechanisms. In this study, we utilized CRISPR epigenome editing of nociceptive neurons to identify mechanisms of degenerative IVD‐induced changes to mechanical nociception and demonstrated the ability of multiplex CRISPR epigenome editing of nociceptive neurons to modulate inflammation‐induced mechanical nociception. Utilizing an in vitro model, we demonstrated degenerative IVD‐produced IL‐6‐induced increases in nociceptive neuron activity in response to mechanical stimuli, mediated by TRPA1, ASIC3, and Piezo2 ion channel activity. Once these ion channels were identified as mediators of degenerative IVD‐induced mechanical nociception, we developed singleplex and multiplex CRISPR epigenome editing vectors that modulate endogenous expression of TRPA1, ASIC3, and Piezo2 via targeted gene promoter histone methylation. When delivered to nociceptive neurons, the multiplex CRISPR epigenome editing vectors abolished degenerative IVD‐induced mechanical nociception while preserving nonpathologic neuron activity. This work demonstrates the potential of multiplex CRISPR epigenome editing as a highly targeted gene‐based neuromodulation strategy for the treatment of discogenic pain, specifically; and, for the treatment of inflammatory chronic pain conditions, more broadly. Multiplex CRISPR epigenome editing of ion channel expression in nociceptive neurons abolished degenerative IVD‐induced mechanical nociception in an in vitro model of discogenic back pain. These results demonstrate multiplex epigenome editing of nociceptive neurons as a potential neuromodulation strategy for discogenic back pain and other chronic pain conditions.
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影响因子：
3
作者：
Burke, JG;Watson, RWG;Fitzpatrick, JM
通讯作者：
Fitzpatrick, JM
影响因子：
168.9
作者：
Freemont, AJ;Peacock, TE;Jayson, MIV
通讯作者：
Jayson, MIV
影响因子：
11.4
作者：
Deval, Emmanuel;Noel, Jacques;Lingueglia, Eric
通讯作者：
Lingueglia, Eric
影响因子：
3.6
作者：
Chen, Jun;Hackos, David H.
通讯作者：
Hackos, David H.
DOI：
10.1002/ejp.732
发表时间：
2016-03
期刊：
European journal of pain (London, England)
影响因子：
--
作者：
Bowles RD;Karikari IO;VanDerwerken DN;Sinclair MS;Bell RD;Riebe KJ;Huebner JL;Kraus VB;Sempowski GD;Setton LA
通讯作者：
Setton LA