Sex-specific regulation of local translation and chronic pain mechanisms in females

女性局部翻译和慢性疼痛机制的性别特异性调节

• 批准号: 10317053
• 负责人: ARMEN N AKOPIAN
• 金额: $ 48.32万
• 依托单位: UNIVERSITY OF TEXAS DALLAS
• 依托单位国家: 美国
• 财政年份: 2018
• 资助国家: 美国
• 起止时间: 2018-04-01 至 2023-12-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10317053
• 关键词: Ablation; Acute; Afferent Neurons; Affinity Chromatography; Area; Axon; Basic Science; Biological; Chronic inflammatory pain; Clinical Management; Custom; Data; Dependence; Estrogens; Female; Foundations; Genes; Genetic Translation; Goals; Gonadal Hormones; Gonadal Steroid Hormones; Hormone Receptor; Hypersensitivity; Interleukin-6; Knowledge; Lead; Literature; Maintenance; Measures; Messenger RNA; Modeling; Mus; Neuronal Plasticity; Neurons; Nociception; Nociceptors; Pain; Patients; Play; Population; Price; Principal Investigator; Prolactin; Prolactin Receptor; Protein Biosynthesis; Regulation; Research; Ribosomes; Role; Scheme; Sensory; Sex Differences; Signal Transduction; Spinal Cord; Synapses; Target Populations; Testing; Therapeutic; Transcriptional Regulation; Translating; Translations; Transportation; Untranslated Regions; base; cell type; chronic pain; chronic pain management; chronic painful condition; defined contribution; dimorphism; gene function; in vivo; innovation; live cell imaging; male; mouse genetics; new therapeutic target; next generation sequencing; novel; pain chronification; personalized medicine; recruit; remote control; sex; sexual dimorphism; therapeutic target; translational potential; treatment strategy

Despite recent advances in our understanding of pain mechanisms, there has been little-to-no overall improvement in the clinical management of chronic pain. It is now recognized that effective chronic pain management depends on key biological variables, especially patient sex. Hence, there is an urgent need to customize chronic pain management schemes based on sex-specific pain mechanisms. Accordingly, our long-term goal is to define sex-dependent mechanisms controlling pain chronicity, and utilize this knowledge to develop sex-specific therapeutics for more effective chronic pain management. Gonadal hormones (GnH) play a key role in sex-dependent regulation of pain mechanisms. There is a gap in knowledge pertaining to how GnH regulate pain chronicity. The objective of this proposal is to identify regulatory mechanisms recruited by GnH for sex-dependent control of pain chronicity. Based on the existing literature and our preliminary data, we propose an entirely novel regulatory mechanism for sexual dimorphisms in chronic pain plasticity wherein the transition from acute to chronic pain is governed by remote control of gene function via GnH-dependent local translation. Our preliminary data suggests that the prolactin receptor (Prlr) may be a linchpin in this mechanism. Prlr is locally translated in females but not males in nociceptor terminals where it contributes strongly to pain plasticity exclusively in females. For instance, sensory neuronal specific Prlr ablation leads to a suppression of IL-6-induced hypersensitivity only in females. Moreover, Prolactin (PRL)-induced hyperalgesic priming, which models the transition from acute to chronic pain, is dramatically enhanced in females compared to males. Therefore, our central hypothesis is that sex- specific regulation of the transition to chronic pain occurs via continuous local translation in nociceptor terminals of mRNAs such as Prlr, and this is fundamentally controlled by gonadal hormones. The proposed study will: 1) greatly expand our knowledge of mechanisms controlling chronicity of pain conditions in females; and 2) provide translational potential by offering therapeutic targets for sex- based chronic pain management. Our hypothesis is tested by interconnected yet independent aims. Aim 1 defines the contribution of local translation in nociceptive terminals, GnH and Prlr in sex-dependent regulation of hyperalgesic priming. Aim 2 examines the involvement of GnH in sex-specific local translation. Aim 3 identifies Prlr sequence motifs controlling sex-specific local translation in nociceptor terminals. The proposed study is innovative because it defines the conceptually novel sex-specific regulatory mechanisms for neuronal plasticity underlying chronic pain in females with technically innovative mouse genetics. The proposed research is significant as it advances our understanding of sex differences in chronic pain mechanisms – an understudied area where increasing basic science knowledge has the potential to lead to better therapeutics.

尽管我们对疼痛机制的理解最近取得了进展，但总体上还没有什么进展。 改善慢性疼痛的临床管理现在已经认识到慢性疼痛是有效的。 管理取决于关键的生物学变量，尤其是患者性别，因此迫切需要。 根据特定性别的疼痛机制定制慢性疼痛管理方案。 长期目标是定义控制疼痛慢性的性别依赖性机制，并利用这些知识 开发针对性别的疗法以更有效地管理慢性疼痛。 在疼痛机制的性别依赖性调节中发挥关键作用，但相关知识存在空白。 GnH 如何调节疼痛慢性性 本提案的目的是确定调节机制。 根据现有文献和我们的研究，由 GnH 招募用于性别依赖性疼痛慢性控制。 根据初步数据，我们提出了一种全新的慢性性别二态性调节机制 疼痛可塑性 从急性疼痛到慢性疼痛的转变是由基因的远程控制控制的 我们的初步数据表明，催乳素受体 (Prlr) 通过 GnH 依赖性局部翻译发挥作用。 Prlr 可能是该机制的关键，在女性伤害感受器中局部翻译，但在男性中则不然。 它对女性的疼痛可塑性有很大贡献，例如感觉。 神经元特异性 Prlr 消融仅在女性中抑制 IL-6 诱导的超敏反应。 此外，催乳素（PRL）诱导的痛觉过敏启动，模拟了从急性到慢性的转变。 与男性相比，女性的疼痛显着增强，因此，我们的中心假设是性别。 向慢性疼痛转变的具体调节是通过持续的局部翻译发生的 mRNA 的伤害感受器末端，例如 Prlr，这从根本上是由性腺控制的 拟议的研究将：1）极大地扩展我们对控制慢性机制的认识。 女性疼痛状况的研究；2）通过提供性治疗目标来提供转化潜力 我们的假设通过相互关联但独立的目标 1 进行了检验。 定义了伤害性末梢局部翻译、GnH 和 Prlr 在性别依赖性中的贡献 目标 2 检查 GnH 在性别特异性局部翻译中的参与。 目标 3 鉴定了控制伤害感受器末端性别特异性局部翻译的 Prlr 序列基序。 拟议的研究具有创新性，因为它定义了概念上新颖的性别特异性调节机制 通过技术创新的小鼠遗传学，研究女性慢性疼痛背后的神经元可塑性。 拟议的研究意义重大，因为它增进了我们对慢性疼痛性别差异的理解 机制——一个未被充分研究的领域，增加基础科学知识有可能导致 更好的治疗方法。

项目成果

Temporal and sex differences in the role of BDNF/TrkB signaling in hyperalgesic priming in mice and rats.

BDNF/TrkB 信号在小鼠和大鼠痛觉过敏启动中的作用存在时间和性别差异。

• 发表时间: 2019-01
• 作者: Moy, Jamie K;Szabo;Tillu, Dipti V;Megat, Salim;Pradhan, Grishma;Kume, Moeno;Asiedu, Marina N;Burton, Michael D;Dussor, Gregory;Price, Theodore J
• 通讯作者: Price, Theodore J

Dural Calcitonin Gene-Related Peptide Produces Female-Specific Responses in Rodent Migraine Models.

硬脑膜降钙素基因相关肽在啮齿动物偏头痛模型中产生女性特异性反应。

• 发表时间: 2019
• 作者: Avona, Amanda;Burgos;Burton, Michael D;Akopian, Armen N;Price, Theodore J;Dussor, Gregory
• 通讯作者: Dussor, Gregory

Sensitization of small-diameter sensory neurons is controlled by TRPV1 and TRPA1 association.

小直径感觉神经元的敏化由 TRPV1 和 TRPA1 关联控制。

• 发表时间: 2020
• 作者: Patil, Mayur J;Salas, Margau;Bialuhin, Siarhei;Boyd, Jacob T;Jeske, Nathaniel A;Akopian, Armen N
• 通讯作者: Akopian, Armen N

Repetitive stress in mice causes migraine-like behaviors and calcitonin gene-related peptide-dependent hyperalgesic priming to a migraine trigger.

小鼠的重复性压力会导致偏头痛样行为，以及降钙素基因相关的肽依赖性痛觉过敏引发偏头痛。

• 发表时间: 2020
• 影响因子: 7.4
• 作者: Avona, Amanda;Mason, Bianca N;Lackovic, Jacob;Wajahat, Naureen;Motina, Marina;Quigley, Lilyana;Burgos;Moldovan Loomis, Cristina;Garcia;Akopian, Armen N;Price, Theodore J;Dussor, Gregory
• 通讯作者: Dussor, Gregory

Sex-stratified genome-wide association study of multisite chronic pain in UK Biobank.

英国生物银行对多部位慢性疼痛进行性别分层全基因组关联研究。

• 发表时间: 2021-04
• 影响因子: 4.5
• 作者: Johnston, Keira J A;Ward, Joey;Ray, Pradipta R;Adams, Mark J;McIntosh, Andrew M;Smith, Blair H;Strawbridge, Rona J;Price, Theodore J;Smith, Daniel J;Nicholl, Barbara I;Bailey, Mark E S
• 通讯作者: Bailey, Mark E S