TLR Transduction of Dysbiotic Pelvic Pain

慢性盆腔疼痛使人衰弱，困扰着美国数百万患者，但盆腔疼痛 病因和有效的治疗方法仍然难以捉摸。小胶质细胞是中枢神经系统免疫细胞 在疼痛中发挥重要作用，并准备对微生物群的变化做出反应，但 小胶质细胞在盆腔疼痛中的作用尚未得到充分描述。同样，微生物组影响许多 生物过程，最近被认为可以调节疼痛，我们已经确定了肠道 盆腔疼痛患者的生态失调和临床相关的盆腔疼痛小鼠模型。小胶质细胞可以 凭借 Toll 样受体转导微生物组信号，但它们在介导盆腔中的作用 微生物群对疼痛的调节尚未被探索。在这里，我们将评估 小胶质细胞对临床相关盆腔疼痛模型中微生物群的反应。我们假设 TLR4 介导小胶质细胞对肠道微生物群的反应。我们将使用两个测试这个假设 模拟假设的不同潜在机制的临床相关小鼠模型 泌尿系统盆腔疼痛的病因、感染模型和遗传易感性模型。瞄准 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性中的作用 功能并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 介导的疼痛。在目标 3 中，我们将检查小胶质细胞对微生物群的反应。在一起，这些 严格和创新的研究将提供小胶质细胞中 TLR4 的首次表征 盆腔疼痛对微生物群的反应，从而为未来的益生菌铺平道路 泌尿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.