Regulation of TRPV1 Activities by a Sexually Dimorphic Mechanism

性二态机制对 TRPV1 活性的调节

• 批准号: 9764343
• 负责人: Kenneth M Hargreaves
• 金额: $ 38.13万
• 依托单位: UNIVERSITY OF TEXAS HLTH SCIENCE CENTER
• 依托单位国家: 美国
• 财政年份: 2016
• 资助国家: 美国
• 起止时间: 2016-09-01 至 2021-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9764343
• 关键词: Address; Afferent Neurons; Antibodies; Biopsy; C3AR1 gene; Capsaicin; Cells; Complement; Complement 3a; Complement 5a; Complex; Data; Dental Pulp; Detection; Endothelium; Female; Fiber; Fibroblasts; Fostering; GTP-Binding Proteins; Goals; Healthcare; Human; Immune; Inflammation; Knowledge; Light; Lipids; Mass Spectrum Analysis; Mediating; Methods; Modeling; Molecular; Neurons; Nociceptors; Orofacial Pain; Pain; Pain Disorder; Pain intensity; Pattern; Peptides; Peripheral; Pharmacology; Policies; Prevalence; Proteins; Pulpitis; Rattus; Regulation; Research; Rodent; Serotonin; Signal Pathway; Signal Transduction; Stimulus; TRPV1 gene; Therapeutic; Tissue Model; Tissues; Trigeminal System; United States National Institutes of Health; Woman; base; cell type; experience; gel electrophoresis; human female; human male; human tissue; innovation; knock-down; knockout animal; men; novel; programs; receptor; response; serotonin receptor; sex; sexual dimorphism

Numerous studies indicate that women and men differ in prevalence of pain disorders or pain intensity, possibly due to sexually dimorphic differences in detection, processing or responses to noxious stimuli. Here, we propose to study a peripheral sexually dimorphic pain mechanism that occurs in humans. The importance of this complex problem has been emphasized by recent NIH policies (NOT OD 15-102). The objective here is to determine the effects of serotonin (5HT), applied to dental pulp biopsies from women versus men, on activation of capsaicin-sensitive nociceptors, and the mechanisms mediating this response. Our central hypothesis is that 5-HT preferentially releases complement peptides C3a or C5a from peripheral tissues of women compared to men, leading to a sexually dimorphic increase in TRPV1 activities in trigeminal (TG) sensory neurons. This central hypothesis is based on substantial novel preliminary data demonstrating that 5HT produces a sexually dimorphic difference in capsaicin activation of human peptidergic fibers via release of complement peptides. The Aims will: Specific Aim #1: Determine the cell type expressing C3a, C5a, C3aR, & C5aR in female versus male human dental pulp. Additional studies will determine the effects of inflammation (irreversible pulpitis) on expression and release of C3a and C5a from female and male human tissues. Specific Aim #2: Determine the 5-HT receptor subtype(s) and G-protein and effector signaling pathways mediating 5-HT-evoked release of C3a and C5a from female and male human tissues. Specific Aim #3: Determine the receptors, G-protein and effector signaling pathways mediating C3a-and C5a-evoked increase in activities of capsaicin-sensitive neurons. The central hypothesis is highly innovative and, if supported, would have an important positive impact on the field since it supports a new model for sexually dimorphic pain mechanisms with therapeutic implications. Moreover, the use of isolated human tissue biopsies and primary neuronal cultures fosters studies on the cellular mechanisms mediating this sexually dimorphic effect and increases translational significance.

大量研究表明，女性和男性在疼痛障碍的患病率或疼痛强度方面存在差异， 可能是由于在检测、处理或对有害刺激的反应方面存在性别差异。这里, 我们建议研究一种发生在人类身上的外周性二形性疼痛机制。它的重要性 NIH最近的政策(而不是OD 15-102)强调了这一复杂问题的重要性。这里的目标是 是为了确定5-羟色胺(5-羟色胺)对女性和男性牙髓活检的影响 辣椒素敏感伤害性感受器的激活，以及介导这一反应的机制。 我们的中心假设是5-羟色胺优先从外周释放补体多肽C3a或C5a 与男性相比，女性的组织中TRPV1活性的性二态增加 三叉神经(TG)感觉神经元。这一中心假设是基于大量新奇的初步数据 证明5-羟色胺在人类辣椒素激活中产生性别二态差异 多肽能纤维通过释放补体多肽。目标将： 特定目标#1：确定女性与男性表达C3a、C5a、C3aR和C5aR的细胞类型 牙髓。其他研究将确定炎症(不可逆性牙髓炎)对表达的影响 以及从女性和男性人体组织中释放C3a和C5a。 具体目标2：确定5-羟色胺受体亚型(S)和G蛋白及效应信号通路 介导5-羟色胺诱导的C3a和C5a从女性和男性人体组织中释放。 具体目标#3：确定介导C3a和C3a的受体、G蛋白和效应信号通路 C5a可引起辣椒素敏感神经元活动增加。 中心假说是高度创新的，如果得到支持，将对 这是因为它支持一种具有治疗意义的性二态疼痛机制的新模型。 此外，分离的人体组织活检和原代神经元培养的使用促进了对 调节这种性别二态效应的细胞机制增加了翻译意义。