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

尿路上皮稳态和间质性膀胱炎/膀胱疼痛综合征中特殊间充质的信号整合

• 批准号: 10583133
• 负责人: PHILIP A BEACHY
• 金额: $ 179.94万
• 依托单位: STANFORD UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2022
• 资助国家: 美国
• 起止时间: 2022-09-24 至 2025-08-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10583133
• 关键词: Absence of pain sensation; Address; Affect; Afferent Neurons; Animal Model; Atlases; Biopsy; Bladder; Bladder Tissue; Blood Circulation; Calcitonin Gene-Related Peptide; Catalogs; Cells; Clinical; Coupled; Cues; Data; Development; Diagnosis; Disease; Epithelial; Erinaceidae; Estrogens; Etiology; Flare; Frequencies; Functional disorder; Genetic; Genetic Models; Growth; Homeostasis; Human; Hyperactivity; Increased frequency of micturition; Injury; Instruction; Interstitial Cystitis; Intervention; Investigation; Lesion; Life; Maintenance; Mesenchymal; Mesenchyme; Molecular; Mus; Natural regeneration; Nerve; Neurons; Neuropeptides; Nociception; Opiate Addiction; Opioid; Output; Pain; Pain management; Pathogenesis; Pathologic; Pathway interactions; Patients; Pelvic Pain; Permeability; Pharmacology; Physiology; Plant Roots; Population Heterogeneity; Production; Regulation; Risk; Role; SHH gene; Sampling; Sensory; Signal Pathway; Signal Transduction; Specific qualifier value; Stimulus; Sum; Symptoms; Techniques; Testing; Urinary tract; Urinary tract infection; Urination; Urothelium; Validation; Woman; addiction; afferent nerve; base; cell type; diagnostic criteria; effective therapy; insight; meetings; mouse genetics; mouse model; nerve supply; neurotrophic factor; new therapeutic target; opioid use; pressure; programs; repaired; response; sexual dimorphism; signal processing; single-cell RNA sequencing; stem cells; therapeutic target; transcriptomics

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.

概括 间质性膀胱炎/膀胱疼痛综合征 (IC/BPS) 是一种病因不明的使人衰弱的疾病，影响 数百万人，其中估计有 2.7-6.3% 的女性受到不成比例的影响，符合诊断标准 IC/BPS 的特点是持续性骨盆疼痛、压力或尿道不适。 并伴有尿急和尿频增加，这些症状对患者来说具有很大的破坏性。 日常生活中，当前的治疗方法无法解决 IC/BPS 的根本原因，这仍然是一个谜。 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 诊断后一个月内的患者，存在显着的成瘾风险。 虽然其发病机制尚不清楚，但 IC/BPS 通常与膀胱感觉有关 过度神经支配，这与对压力或有害刺激敏感性增加的临床表现相符。 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， 急性发作（高达 1/3）与损伤尿路上皮的尿路感染之间的关联表明， 伴有 Hunner 病变的严重 IC/BPS 中尿路上皮屏障几乎完全丧失（10-20% 的患者）。 小鼠数据，包括 scRNA-Seq（单细胞 RNA 测序），精确定位膀胱的特殊区室 间质在调节膀胱感觉神经支配和尿路上皮完整性中发挥作用。 特殊的间充质，称为 SAM（感觉神经相关间充质），似乎可以整合信号传导 来自全身循环、邻近膀胱细胞类型（包括尿路上皮）的输入以及来自 伤害感受神经末端产生间充质指令集，该指令集是性别二态性的基础 膀胱伤害感受和尿路上皮完整性的维持。 我们的初步数据还提供了基于正常样本的 scRNA-Seq 的分子纲要 人类和 IC/BPS 患者膀胱的该 IC/BPS 细胞图谱表明 SAM 在信号处理方面存在功能障碍。 整合可能构成一个核心共同特征，将不同的表现形式统一起来 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，以包括 基于这些发现的进一步研究可能会识别 SAM 特异性。 我们提案的目标 1 将重点关注局部信号通路作为 IC/BPS 干预的新治疗靶点。 以及引发 SAM 产生神经营养素的全身信号，而 Aim 2 提供了初步研究 表明支配膀胱的感觉神经元可以深刻影响尿路上皮，可能通过 神经肽向 SAM 发出信号，用无毒药物调节这些信号通路。 如目标 3 中所述，IC/BPS 动物模型将为有效的新疗法提供基础，这可能会 消除在疼痛管理中使用阿片类药物的需要，从而消除成瘾的风险。