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的患病率或疼痛强度方面存在差异，