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.

许多研究表明，女性和男性在疼痛障碍或疼痛强度的患病率方面存在差异， 这可能是由于在对有害刺激的检测、处理或反应方面的两性差异。在这里， 我们建议研究一种发生在人类的外周性二态性疼痛机制。的重要性 最近的NIH政策强调了这一复杂问题的重要性（而不是OD 15-102）。这里的目标 是为了确定血清素（5 HT）的影响，应用于女性与男性的牙髓活检， 辣椒素敏感性伤害感受器的激活，以及介导这种反应的机制。 我们的中心假设是5-HT优先从外周血释放补体肽C3 a或C5 a， 与男性相比，女性组织中TRPV 1活性的性二态性增加， 三叉神经（TG）感觉神经元。这一中心假设是基于大量新颖的初步数据 证明5 HT在辣椒素激活人类的细胞中产生性二态性差异， 肽能纤维通过释放补体肽。目标将： 具体目标#1：确定女性与男性中表达C3 a、C5 a、C3 aR和C5 aR的细胞类型 牙髓进一步的研究将确定炎症（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C3 a和C5 a。 具体目标#2：确定5-HT受体亚型和G蛋白和效应物信号传导途径 介导5-HT诱发的C3 a和C5 a从女性和男性人体组织的释放。 具体目标#3：确定受体、G蛋白和效应信号通路介导C3 a-和 c5 a诱发辣椒素敏感神经元活动的增加。 核心假设具有高度创新性，如果得到支持，将对全球化产生重要的积极影响。 因为它支持了一种新的具有治疗意义的性二态性疼痛机制模型。 此外，使用分离的人体组织活检和原代神经元培养物促进了对神经元的研究。 细胞机制介导这种性二态效应并增加翻译意义。