Lipoteichoic acid mediated modulation of chronic 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， 一株健康人前列腺分泌的表皮葡萄球菌 志愿者可以通过尿道内给药，迅速抑制病原性免疫 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，

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.