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：
10539502
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/10539502
关键词：
Accounting Afferent Neurons American Animal Model Anogenital region Autoimmune Bacteria Behavioral Biological Assay CD4 Positive T Lymphocytes Calcium Categories Cells 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 Lead Ligands Measures Mechanics Mediating Medical Modeling Morbidity - disease rate Mus Neuraxis Neurons Nociception Opioid Peptide Outpatients PTPN6 gene Pain Pain management Pathogenicity Pathway interactions Patients Pelvic Pain Peptide Receptor Peripheral Peripheral Nervous System Phosphorylation Positioning Attribute Primary Care Physician Prostate Receptor Gene Role Signal Induction Signal Transduction Slice Source Spinal Ganglia Staphylococcus epidermidis Syndrome System TLR2 gene Testis Therapeutic United States Visit 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 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，前列腺炎占每年200万个门诊就诊，包括 1％的初级保健医生。慢性前列腺炎/慢性骨盆疼痛综合征（CP/CPP）在临床上以排尿和疼痛为特征，睾丸，阴茎，和上木座区域。尽管CPP占所有慢性前列腺炎的90％，但是缺乏有效的疗法。在动物模型中，慢性骨盆疼痛显示为与免疫失调和伤害性途径的激活有关周围和中枢神经系统。我们以前证明了源自健康人的前列腺的表皮葡萄球菌表皮菌株志愿者可以在内部递送以快速抑制致病性免疫反应并导致骨盆疼痛的深刻改善。在最后一个时期授予我们使用该隔离，纯化和概括了使用该效果整个细菌的脂甲酸（Selta）成分。我们证明了通过诱导的检查点配体PD-L1的表达来进行免疫调节活性和PD-L2。在支持此应用的初步研究中，我们检查了直接 Selta对背根神经神经元的影响，并确定Selta能够 TLR2依赖于疼痛涉及的稳态神经元途径的激活调制。还证明了Selta治疗以增加神经元中的内源性阿片类药物途径。因此，我们假设Selta可以通过激活调节神经元兴奋性，介导抗伤害感受效应稳态抑制信号传导和内源性阿片类药物途径的诱导。在这个研究我们将剖析这些反伤害感受的新机制使用动物模型组合的途径，离体背根神经节切片记录和体外信号研究。 Selta活动的概念证明将是在人的背根神经节中证明。拟议的研究将提供机械理解Selta如何发挥抗伤害性活性，并将设定 - 作为一种新型的慢性骨盆疼痛的新型尖端治疗的发展阶段。