Signal integration by specialized mesenchyme in urothelial homeostasis and Interstitial Cystitis / Bladder Pain Syndrome

总结 间质性膀胱炎/膀胱疼痛综合征（IC/BPS）是一种病因不明的衰弱性疾病， 数百万人，其中估计有2.7-6.3%的女性符合诊断标准，她们受到的影响尤其严重 的搜索. IC/BPS的特征是持续的骨盆疼痛、压迫或泌尿道引起的不适 并伴有尿急和尿频。这些症状对 日常生活中，目前的治疗未能解决IC/BPS的根本原因，这仍然是个谜。 疼痛管理是治疗的一个重要方面，28%的患者采用阿片类药物镇痛。 患者在诊断后一个月内，表现出明显的成瘾风险。 尽管其发病机制尚不清楚，IC/BPS通常与膀胱感觉神经系统相关， 神经支配过度，这与对压力或伤害性刺激的敏感性增加的临床表现一致。 然而，有效的治疗还必须解决保护性膀胱上皮（尿路上皮）的功能障碍， 如急性发作（高达1/3）与尿路感染的相关性所示， 严重IC/BPS伴Hunner病变（10-20%的患者）的尿路上皮屏障几乎完全丧失。我们 小鼠数据，包括scRNA-Seq（单细胞RNA测序），精确定位了膀胱的一个专门区室， 在膀胱感觉神经支配和尿路上皮完整性的调节中起作用的间充质。这 一种专门的间充质，称为SAM（感觉神经相关间充质），似乎整合信号传导 来自全身循环、来自邻近膀胱细胞类型（包括尿道上皮细胞）和来自 伤害感受神经元末端产生间充质指令集，该指令集是性二态性的基础， 膀胱伤害感受和维持尿路上皮完整性。 我们的初步数据还提出了一个分子纲要的基础上scRNA-Seq的样本，从正常 人和IC/BPS患者膀胱。IC/BPS细胞图谱表明SAM在信号处理中的功能障碍 和一体化可能构成一个中心的共同特点，基础和统一的各种表现， IC/BPS，我们建议通过扩展我们的细胞图谱来确认和扩展这些初步发现， 来自多个疾病阶段的样本。基于这些发现的进一步调查可能会发现SAM特异性 信号通路作为IC/BPS干预的新治疗靶点。我们建议的目标1将侧重于本地 和引起SAM产生神经营养因子的系统信号，而Aim 2提出了初步研究 这表明支配膀胱的感觉神经元可以深刻地影响尿道，可能是通过 神经肽信号传导至SAM。用无毒的药物调节这些信号通路， 如目标3所述，IC/BPS的动物模型将为有效的新治疗提供基础， ·减少阿片类药物用于疼痛管理的必要性，从而消除成瘾的风险。

Summary Interstitial Cystitis/Bladder Pain Syndrome (IC/BPS) is a debilitating disease of unknown etiology that affects millions, with an estimated 2.7-6.3% of women, who are disproportionately affected, meeting the diagnostic criteria. IC/BPS is characterized by persistent pelvic pain, pressure, or discomfort arising from the urinary tract and is accompanied by increased urgency and frequency of urination. These symptoms are highly disruptive to everyday life, and current treatments fail to address the underlying causes of IC/BPS, which remain enigmatic. Pain management is an essential aspect of treatment, and incorporates opioid-based analgesia in 28% of patients within a month of diagnosis, presenting significant risks of addiction. Whereas its pathogenesis remains unclear, IC/BPS is commonly associated with bladder sensory hyperinnervation, which aligns with the clinical picture of increased sensitivity to pressure or noxious stimuli. Effective treatment, however, must also address dysfunction of the protective bladder epithelium (urothelium), as indicated by the association of flare-ups (up to 1/3) with urinary tract infections that injure the urothelium and by the near total loss of the urothelial barrier in severe IC/BPS with Hunner’s lesions (10-20% of patients). Our mouse data, including scRNA-Seq (single cell RNA sequencing), pinpoint a specialized compartment of bladder mesenchyme that functions in the regulation of both bladder sensory innervation and urothelial integrity. This specialized mesenchyme, termed SAM (sensory nerve-associated mesenchyme), appears to integrate signaling inputs from the general circulation, from neighboring bladder cell types including urothelium, and from nociceptive neuronal termini to generate a mesenchymal instruction set that underlies sexual dimorphism in bladder nociception and maintenance of urothelial integrity. Our preliminary data also present a molecular compendium based on scRNA-Seq of samples from normal human and IC/BPS patient bladders. This IC/BPS cell atlas suggests that SAM dysfunction in signal processing and integration may constitute a central common feature underlying and unifying the diverse manifestations of IC/BPS, and we propose to confirm and extend these preliminary findings by expanding our cell atlas to include samples from multiple disease stages. Further investigation based on these findings may identify SAM-specific signaling pathways as novel therapeutic targets for IC/BPS intervention. Aim 1 of our proposal will focus on local and systemic signals that elicit SAM production of neurotrophins, whereas Aim 2 presents preliminary studies showing that sensory neurons innervatint the bladder can profoundly affect the urothelium, likely acting through neuropeptide signaling to SAM. Modulating these signaling pathways with non-toxic pharmacologic agents in animal models of IC/BPS, as outlined in Aim 3, will provide the basis for effective new treatments, which may obviate the need for opioid use in pain management, thereby eliminating the risk of addiction.