TLR Transduction of Dysbiotic Pelvic Pain

在美国，慢性骨盆疼痛使人虚弱，并困扰着数百万患者，但骨盆疼痛 病因和有效的治疗方法仍然难以捉摸。小胶质细胞是发挥作用的中枢神经系统免疫细胞 在疼痛中的重要作用，并准备对微生物区系的变化做出反应，但 小胶质细胞在骨盆疼痛中的作用尚未完全描述。同样，微生物群影响着许多人 生物过程，最近被认为是调节疼痛，我们已经确定肠道 盆腔疼痛患者和临床相关的盆腔疼痛小鼠模型中的生物失调。小胶质细胞可以 通过Toll样受体传递微生物组信号，但它们在骨盆中的中介作用 微生物区系对疼痛的调制还没有被探索过。在这里，我们将评估 临床相关盆腔疼痛模型中的小胶质细胞对微生物区系的反应。我们假设 TLR4介导小胶质细胞对肠道微生物区系的反应。我们将用两个例子来检验这一假设 临床相关的不同潜在机制的小鼠模型，模拟假设 尿路盆腔疼痛的病因、感染模型和遗传易感性模型。在AIM 1，我们将量化小胶质细胞在啮齿动物疼痛反应和认知相关中的作用 功能和定义小胶质细胞表型。在目标2中，我们将定义TLR4在小胶质细胞中的作用- 中介性疼痛。在目标3中，我们将检查小胶质细胞对微生物区系的反应。加在一起，这些 严谨和创新的研究将首次提供TLR4在小胶质细胞中的特征- 微生物区系对盆腔疼痛的依赖性反应，从而为未来的益生菌铺平道路 泌尿外科慢性盆腔疼痛的治疗策略。

Chronic pelvic pain is debilitating and afflicts millions of patients in the U.S., yet pelvic pain etiologies and effective therapies remain elusive. Microglia are CNS immune cells that play significant roles in pain and are poised to respond to changes in microbiota, yet the roles of microglia in pelvic pain are not fully described. Similarly, the microbiome influences many biological processes and is recently appreciated to modulate pain, and we have identified gut dysbiosis in pelvic pain patients and clinically relevant mouse models of pelvic pain. Microglia can transduce microbiome signals by virtue of Toll-like receptors, but their roles in mediating pelvic pain modulation by microbiota have not been explored. Here, we will evaluate the role of microglia responses to microbiota in clinically-relevant models of pelvic pain. We hypothesize that TLR4 mediates microglial responses to gut microbiota. We will test this hypothesis using two clinically relevant mouse models of distinct underlying mechanisms that mimic postulated etiologies of urologic pelvic pain, an infection model and a genetic susceptibility model. In Aim 1, we will quantify the role of microglia in rodent correlates of pain responses and cognitive function and define microglial phenotypes. In Aim 2, we will define the role of TLR4 in microglia- mediated pain. And in Aim 3, we will examine microglial responses to microbiota. Together, these rigorous and innovative studies will provide the first characterization of TLR4 in microglia- dependent pelvic pain responses to microbiota and thus pave the way for future probiotic strategies for the treatment of urologic chronic pelvic pain.