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; 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）是一种令人衰弱的病因疾病，会影响 数百万，估计有2.7-6.3％的妇女受到诊断的影响 标准。 IC/BP的特征是尿路持续骨盆疼痛，压力或不适感 并通过增加的紧迫性和排尿频率来实现。这些符号高度破坏 日常生活和当前的治疗方法无法解决IC/BP的根本原因，这些原因仍然是神秘的。 疼痛管理是治疗的重要方面，并将基于阿片类药物的镇痛纳入28％ 患者在诊断的一个月内提出了很大的成瘾风险。 尽管其发病机理尚不清楚，但IC/BPS通常与膀胱感觉有关 高温作用，与对压力或有害刺激的敏感性增加的临床形象保持一致。 然而，有效的治疗也必须解决受保护膀胱上皮（尿液）的功能障碍， 如爆发（最多1/3）与尿路感染的关联所示 在严重的IC/BPS中，静脉内屏障的总损失（占患者占10-20％）。我们的 鼠标数据，包括SCRNA-SEQ（单细胞RNA测序），查明了膀胱的专门隔室 在调节膀胱感觉神经和尿路上皮完整性的调节中起作用的间质。这 专门的间质，称为SAM（感觉神经相关的间充质），似乎整合了信号传导 来自一般循环的输入，来自邻近的膀胱细胞类型，包括尿路上皮，以及来自 伤害性神经元末端产生一个间充质指令集，该指令是性二态性的基础 膀胱伤害感和尿路上皮完整性的维护。 我们的初步数据还基于正常的样品的screcular compendium 人和IC/BPS患者膀胱。此IC/BPS细胞图块表明信号处理中的SAM功能障碍 一体化可能构成一个主要的共同特征，并统一潜水员的表现形式 IC/BPS，我们建议通过扩展我们的细胞图集以包括 来自多种疾病阶段的样本。基于这些发现的进一步研究可能会鉴定出SAM特定的 信号通路作为IC/BPS干预的新型治疗靶标。我们的建议的目标1将重点放在本地 以及引起SAM产生神经营养蛋白的系统信号，而AIM 2介绍了初步研究 表明膀胱的感觉神经元内伏汀会深刻影响尿路上皮，可能通过 神经肽对SAM的信号传导。用无毒的药物学调节这些信号通路 AIM 3中概述的IC/BP的动物模型将为有效的新疗法提供基础，这可能 消除在疼痛管理中使用阿片类药物的需求，从而消除成瘾的风险。