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Lipoteichoic acid mediated modulation of chronic pain

脂磷壁酸介导的慢性疼痛调节

基本信息

批准号：
10688082
负责人：
PRAVEEN THUMBIKAT
金额：
$ 54.07万
依托单位：
NORTHWESTERN UNIVERSITY AT CHICAGO
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：
2016-08-01 至 2026-06-30
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10688082
关键词：
Ablation Accounting Afferent Neurons American Animal Model Anogenital region Autoimmune Bacteria Behavioral Biological Assay CD4 Positive T Lymphocytes Calcium Categories Cells Central Nervous System Chronic Prostatitis Clinical Cre lox recombination system Development Disease Dynorphins Dysuria Electrophysiology (science)Future Gene Expression Goals Grant Human Human Volunteers Immune Immune response Immunofluorescence Immunologic In Vitro Interleukin-10 Kinetics Knock-out Knockout Mice Ligands Measures Mechanics Mediating Medical Modeling Morbidity - disease rate Mus Neurons Nociception Nociceptors Opioid Peptide Outpatients PTPN6 gene Pain Pain management Pathogenicity Pathway interactions Patients Pelvic Pain Peptide Initiation Factors Peripheral Nervous System Phosphorylation Positioning Attribute Primary Care Physician Prostate Receptor Gene Role Signal Transduction Slice Source Spinal Ganglia Staphylococcus epidermidis Syndrome System TLR2 gene Testis Therapeutic United States Visit antinociception chronic pain chronic pelvic pain commensal bacteria effective therapy endogenous opioids immunoregulation kappa opioid receptors lipoteichoic acid mRNA Expression men mouse model neuronal excitability neuroregulation novel penis preference prodynorphin programmed cell death ligand 1 programmed cell death protein 1 prostatitis receptor receptor function response spontaneous pain

项目摘要

Prostatitis accounts for 2 million outpatient visits per year in the United States, including 1% of those to primary care physicians. Chronic prostatitis/Chronic pelvic pain syndrome (CP/CPPS) is clinically characterized by dysuria and pain in the perineum, testes, penis, and suprapubic region. Despite CPPS accounting for 90% of all chronic prostatitis, there is an absence of effective therapies. In animal models, the chronic pelvic pain is shown to be associated with immune dysregulation and the activation of nociceptive pathways in the peripheral and central nervous system. We previously demonstrated that a commensal Staphylococcus epidermidis strain derived from the prostate of a healthy human volunteer could be delivered intraurethrally to rapidly inhibit the pathogenic immune response and lead to a profound amelioration of pelvic pain. In the last period of this grant we isolated, purified, and recapitulated the anti-nociceptive effects using the lipoteichoic acid (SELTA) component of the whole bacteria. We demonstrated immunomodulatory activity through induced expression of checkpoint ligands PD-L1 and PD-L2. In preliminary studies in support of this application, we examined direct effects of SELTA on dorsal root ganglia neurons and identified that SELTA is capable of TLR2 dependent activation of a homeostatic neuronal pathway involved in pain modulation. SELTA treatment was also demonstrated to increase expression of the endogenous opioid pathway in neurons. We therefore hypothesize that SELTA can mediate anti-nociceptive effects by modulation of neuronal excitability through activation of homeostatic inhibitory signaling and induction of endogenous opioid pathways. In this study we will dissect novel mechanisms underlying activation of these anti-nociceptive pathways using a combination of animal models, ex vivo dorsal root ganglia slice recordings and in vitro signaling studies. Proof of concept for SELTA activity will be demonstrated in human dorsal root ganglia. The proposed studies will provide a mechanistic understanding of how SELTA exerts anti-nociceptive activity and will set- the-stage for its development as a novel cutting-edge therapeutic for chronic pelvic pain.

在美国，前列腺炎每年占200万门诊就诊，包括其中1%是初级保健医生。慢性前列腺炎/慢性骨盆疼痛综合征 (CP/CPPS）的临床特征是排尿困难和会阴、睾丸、阴茎和耻骨上区域。尽管CPPS占所有慢性前列腺炎的90%，缺乏有效的治疗方法在动物模型中，慢性盆腔疼痛被证明是与免疫失调和伤害性通路的激活有关，外周和中枢神经系统。我们以前证明，来源于健康人前列腺的共生表皮葡萄球菌菌株志愿者可以通过尿道内注射来快速抑制病原体免疫反应，并导致盆腔疼痛的深刻改善。在这最后一段时间里，格兰特，我们分离，纯化，并概括了抗伤害性作用，使用脂磷壁酸（SELTA）是整个细菌的组分。我们证明通过检查点配体PD-L1诱导表达的免疫调节活性 PD-L2在支持这一应用的初步研究中，我们直接研究了 SELTA对背根神经节神经元的影响，并确定SELTA能够 TLR 2依赖性激活参与疼痛的稳态神经元通路调变SELTA处理也被证明增加了内源性阿片途径。因此，我们假设SELTA可以通过激活调节神经元兴奋性介导抗伤害性作用稳态抑制信号传导和诱导内源性阿片途径。在这研究中，我们将剖析这些抗伤害性的潜在激活的新机制，使用动物模型、离体背根神经节切片的组合的通路记录和体外信号传导研究。SELTA活动的概念验证将是在人类背根神经节中发现。拟议的研究将提供一个机械理解如何SELTA发挥抗伤害性活动，并将设置- 作为一种新型的治疗慢性盆腔疼痛的尖端疗法，