Cystitis-induced bladder dysfunction and pain

膀胱炎引起的膀胱功能障碍和疼痛

• 批准号: 10090725
• 负责人: MARGARET Ann VIZZARD
• 金额: $ 55.74万
• 依托单位: UNIVERSITY OF VERMONT & ST AGRIC COLLEGE
• 依托单位国家: 美国
• 财政年份: 2021
• 资助国家: 美国
• 起止时间: 2021-01-28 至 2024-12-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10090725
• 关键词: Acute; Address; Affect; Animal Model; Apoptosis; Attenuated; Biological Assay; Bladder; Bladder Dysfunction; Cations; Cells; Chronic; Clinical; Clinical Trials; Conscious; Coupled; Cyclophosphamide; Cystitis; Disease; Dose; Enzyme-Linked Immunosorbent Assay; Esthesia; Event; Exocytosis; Experimental Models; Flare; Frequencies; Functional disorder; Human; Image; Immunohistochemistry; Increased frequency of micturition; Interruption; Interstitial Cystitis; Knockout Mice; Laboratories; Link; MAP Kinase Gene; Mediating; Mediator of activation protein; Micturition Reflex; Modeling; Mus; NGFR Protein; Pain; Pain Disorder; Pathway interactions; Patients; Pelvic Pain; Pelvis; Pharmacology; Psychological Stress; Publishing; Quality of life; Recovery; Research; Resistance; Role; Sensory; Signal Pathway; Signal Transduction; Signs and Symptoms; Spinal Ganglia; Spinal cord injury; Stress; Structure; Symptoms; System; Testing; Tissues; Transcript; Transducers; Transgenic Mice; Urination; Urothelial Cell; Urothelium; Vanilloid; Work; afferent nerve; bladder pain; chronic pelvic pain; confocal imaging; effective therapy; innovation; insight; interdisciplinary approach; member; mouse model; multidisciplinary; neurochemistry; novel; overexpression; pain perception; pain reduction; prevent; protein expression; receptor; response; small molecule; urinary

Project Summary/Abstract Bladder Pain Syndrome (BPS)/Interstitial Cystitis (IC) is a chronic pelvic pain disorder with at least one urinary symptom and the perception that the pain originates from the bladder. Stress exacerbates symptoms of BPS/IC. Despite intense research, we lack understanding of how structural and functional changes in the micturition reflex are linked to BPS/IC and how stress exacerbates symptoms, thus impeding effective therapies. Addressing these challenges requires, in part: (1) a novel hypothesis involving NGF/TrkA/MAPK signaling for downstream transient receptor potential cation channel subfamily vanilloid member 4 (TRPV4)/Ca2+ activation in the sensory components of the micturition reflex; (2) innovative and multidisciplinary approaches; and (3) animal models that recapitulate the clinical signs/symptoms of BPS/IC including symptom exacerbation (flares) precipitated by psychological stress. Our laboratory is unique in the complementary use of several relevant models to reinforce our studies including (e.g., cyclophosphamide (CYP)-induced cystitis, transgenic mice with chronic, urothelial overexpression of NGF (NGF-OE), repeated, low dose CYP (alone insufficient to produce significant symptoms) coupled with repeated variate stress (RVS) to assess how stress can exacerbate disease. Our overall hypothesis is that increases in urinary frequency and pelvic sensation that accompany BPS/IC reflect increased expression, function and interactions of neurochemical mediators and the sensory transducer, TRPV4, in the sensory components of the micturition reflex that favor a pro-excitatory state. Building from our previous work, the maladaptive role(s) of NGF/TrkA/p75NTR signaling and downstream activation of TRPV4/Ca2+ in the sensory components of the micturition reflex will be assessed as contributory mechanisms to BPS/IC. Aim 1: Determine if interrupting NGF/TrkA/p75NTR signaling pathways reduces voiding frequency and pelvic pain by: reducing (1) urothelial Ca2+ events; (2) urothelial ATP release and (3) bladder afferent activity. Further interrupting NGF/p75NTR signaling reduces voiding frequency by: (1) reducing urothelial cell apoptosis; (2) promoting urothelial cell recovery and (3) maintaining transepithelial resistance. Aim 2: Determine if disruption of NGF signaling in the micturition pathway has short- and long-term consequences on TRPV4/Ca2+ function in BPS/IC-like symptoms. The acute NGF-mediated TRPV4/Ca2+ BPS/IC-related responses include heightened urothelial Ca2+ signaling, urothelial ATP secretion and bladder afferent nerve activity. Maladaptive, long-term NGF signaling promotes BPS/IC by increasing TRPV4 transcript and protein expression. Using three models with BPS/IC-like symptoms and a multidisciplinary, cell-tissue- systems experimental approach, we will determine: (1) underlying structural and functional changes contributory to BPS/IC-like symptoms; (2) the influence of psychological stress on bladder function and pain and (3) novel treatments.

项目摘要/摘要 膀胱疼痛综合征（BPS）/间质性膀胱炎（IC）是一种慢性骨盆疼痛障碍，至少有一次尿 症状和对疼痛起源于膀胱的看法。压力加剧了 BPS/IC。尽管进行了深入的研究，但我们对结构和功能的变化缺乏了解 排尿反射与BPS/IC有关，以及压力如何加剧症状，从而阻碍有效 疗法。解决这些挑战需要部分：（1）涉及NGF/TRKA/MAPK的新假设 下游瞬态受体电势阳离子通道亚家族香草的信号传导4 （TRPV4）/Ca2+在排尿反射的感觉成分中的激活； （2）创新和多学科 方法； （3）概括BPS/IC的临床体征/症状的动物模型包括症状 由心理压力促成的加重（耀斑）。我们的实验室在互补使用方面是独一无二的 在几种相关模型中加强我们的研究，包括（例如环磷酰胺（CYP）诱导的膀胱炎） NGF（NGF-OE）的慢性尿路上皮过表达的转基因小鼠重复，低剂量CYP（单独 不足以产生重大症状）以及重复的变异应力（RV），以评估压力如何 会加剧疾病。我们的总体假设是，尿频和骨盆感觉增加了 伴随BPS/IC反映了神经化学介体和 感觉传感器TRPV4，在排尿反射的感觉成分中，有利于促兴趣 状态。从我们以前的工作，NGF/TRKA/p75ntr信号和下游的不良适应性角色建设 排尿反射的感觉成分中TrPv4/Ca2+的激活将被评估为贡献 BPS/IC的机制。 AIM 1：确定中断NGF/TRKA/P75NTR信号通路是否会降低空隙 频率和骨盆疼痛通过：减少（1）尿路上皮Ca2+事件； （2）尿路上皮ATP释放和（3）膀胱 传入活动。进一步中断NGF/P75NTR信号传导可降低空隙频率：（1）降低 尿路上皮细胞凋亡； （2）促进尿路上皮细胞的恢复和（3）维持旋转抗性。 AIM 2：确定在排尿途径中NGF信号的破坏是否具有短期和长期 BPS/IC样症状中TRPV4/CA2+功能的后果。急性NGF介导的TRPV4/CA2+ BPS/IC相关的响应包括尿路上皮CA2+信号加剧，尿路上皮ATP分泌和膀胱 传入神经活动。不良适应性的长期NGF信号通过增加TRPV4转录本来促进BPS/IC 和蛋白质表达。使用三种具有BPS/IC样症状的模型和一个多学科的细胞 - 组织 - 系统实验方法，我们将确定：（1）基础结构和功能变化 促进BPS/IC样症状； （2）心理压力对膀胱功能和疼痛的影响 （3）新型治疗方法。