Regulation of TRPV1 Activities by a Sexually Dimorphic Mechanism

性二态机制对 TRPV1 活性的调节

基本信息

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
项目类别：
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

项目摘要

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，男女在疼痛障碍或疼痛强度的患病率上有所不同，可能是由于性二态性差异在检测，处理或对有害刺激的反应中的差异。这里，我们建议研究人类发生的外围性二态疼痛机制。重要性最近的NIH政策（不是OD 15-102）强调了这个复杂的问题。这里的目标是为了确定5-羟色胺（5HT）的影响，应用于女性与男性的牙浆活检辣椒素敏感的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优先从外围释放补体C3A或C5A 与男性相比，女性组织的组织，导致TRPV1活性的性二态增加三叉神经（TG）感觉神经元。该中心假设基于大量新的初步数据证明5HT在人的辣椒素激活中产生性二态差异肽纤维通过释放补体肽。目的将：特定目的＃1：确定表达C3A，C5A，C3AR和C5AR的细胞类型，女性与男性人类牙浆。其他研究将确定炎症（不可逆性肺炎）对表达的影响以及从雌性和男性人体组织中释放C3A和C5A。特定目标＃2：确定5-HT受体亚型和G蛋白和效应子信号通路从女性和男性组织中介导5-HT诱发的C3A和C5A的释放。特定目的＃3：确定受体，G蛋白和效应子信号传导途径介导C3A，并且 C5A引起的辣椒素敏感神经元活动的增加。中心假设具有很高的创新性，如果得到支持，将对由于它支持具有治疗意义的性二态疼痛机制的新模型。此外，使用孤立的人体组织活检和原发性神经元培养物促进了有关该研究的研究细胞机制介导这种性二态效应并增加了翻译意义。