TLR Transduction of Dysbiotic Pelvic Pain

生态失调性盆腔疼痛的 TLR 转导

• 批准号: 10737191
• 负责人: David J Klumpp
• 金额: $ 58.63万
• 依托单位: NORTHWESTERN UNIVERSITY AT CHICAGO
• 依托单位国家: 美国
• 财政年份: 2023
• 资助国家: 美国
• 起止时间: 2023-08-21 至 2027-06-30
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10737191
• 关键词: Ablation; Acute Pain; Biological Markers; Biological Process; Cells; Chronic Prostatitis; Circulation; Clinic; Clinical; Cues; Data; Development; Diagnosis; Disease; Endotoxins; Etiology; Exhibits; Female; Fostering; Future; Gene Expression; Genetic; Genetic Predisposition to Disease; Immune; In Vitro; Infection; Interstitial Cystitis; Knockout Mice; Leaky Gut; Mediating; Mediator; Microglia; Modeling; Morbidity - disease rate; Morphology; Mus; Neurons; Pain; Pathogenesis; Pathogenicity; Patients; Pelvic Pain; Phenotype; Play; Probiotics; Reporting; Rodent; Rodent Model; Role; Serum; Signal Transduction; Site; Symptoms; TLR4 gene; Testing; Toll-like receptors; Transducers; attenuation; chronic pain; chronic pelvic pain; clinically relevant; cognitive function; conditional knockout; dysbiosis; effective therapy; fecal transplantation; genetic approach; glial activation; gut dysbiosis; gut microbiota; in vivo; innovation; men; microbial; microbial products; microbiome; microbiota; mouse model; novel; pain behavior; pain patient; pain score; pharmacologic; pre-clinical; probiotic therapy; response; targeted treatment; transcriptome sequencing; treatment strategy; urologic; urologic chronic pelvic pain syndrome

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.

慢性骨盆疼痛使人衰弱，折磨着美国数百万的患者，但骨盆疼痛 病因和有效的治疗仍然难以捉摸。小胶质细胞是中枢神经系统的免疫细胞， 在疼痛中起重要作用，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还没有得到充分的描述。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 在骨盆疼痛患者和骨盆疼痛的临床相关小鼠模型中的微生态失调。小胶质细胞可以 微生物组通过Toll样受体发出信号，但它们在介导盆腔炎中的作用 还没有研究过微生物群对疼痛的调节。在这里，我们将评估 小胶质细胞对盆腔疼痛临床相关模型中微生物群的反应。我们假设 TLR 4介导小胶质细胞对肠道菌群的反应。我们将用两个例子来检验这个假设。 具有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学、感染模型和遗传易感性模型。在Aim中 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， 功能和定义小胶质细胞表型。在目标2中，我们将定义TLR 4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。所有这些 严谨和创新的研究将提供小胶质细胞中TLR 4的第一个特征， 依赖于微生物群的盆腔疼痛反应，从而为未来的益生菌铺平道路 泌尿系慢性盆腔疼痛的治疗策略。