Lipoteichoic acid mediated modulation of chronic pain

前列腺炎在美国每年的门诊量为200万人次，其中包括 其中1%给了初级保健医生。慢性前列腺炎/慢性盆腔疼痛综合征 慢性前列腺炎(CP/CPPS)的临床特征是会、睾丸、阴茎、 和耻骨上区域。尽管慢性前列腺炎占所有慢性前列腺炎的90%，但有 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。我们之前演示了一个 来源于健康人前列腺的共生性表皮葡萄球菌菌株 志愿者可经尿路快速抑制病原性免疫 对盆腔疼痛有显著的改善作用。在这最后一段时间里 格兰特我们分离、提纯和概括了抗伤害性作用 全菌的脂磷壁酸(SELTA)成分。我们演示了 通过诱导表达检查点配体PD-L1的免疫调节活性 和PD-L2。在支持这一应用的初步研究中，我们研究了直接 SELTA对背根神经节神经元的影响及鉴定 依赖TLR2激活参与疼痛的动态平衡神经通路 调制。SELTA治疗也被证明增加了 神经元中的内源性阿片途径。因此，我们假设SELTA可以 激活调节神经元兴奋性介导抗伤害性效应 动态平衡抑制信号和内源性阿片通路的诱导。在这 研究中，我们将剖析这些抗伤害性感受器激活的新机制 采用动物模型结合的途径，离体背根神经节切片 录音和体外信号研究。SELTA活动的概念验证将是 在人背根神经节中有表达。拟议的研究将提供一个 对SELTA如何发挥抗伤害性活动并将其设定为 将其发展成为治疗慢性盆腔疼痛的新型尖端疗法的阶段。

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.