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.

项目总结/摘要 膀胱疼痛综合征（BPS）/间质性膀胱炎（IC）是一种慢性盆腔疼痛疾病， 症状和疼痛源于膀胱的感觉。压力会加剧 BPS/IC。尽管进行了大量的研究，但我们缺乏对细胞内结构和功能变化的了解。 排尿反射与BPS/IC有关，以及压力如何加剧症状，从而阻碍有效的 治疗解决这些挑战需要，部分：（1）一个新的假设，涉及NGF/TrkA/MAPK 下游瞬时受体电位阳离子通道亚家族香草素成员4的信号传导 （TRPV 4）/Ca 2+激活排尿反射的感觉成分;（2）创新和多学科 方法;和（3）再现BPS/IC的临床体征/症状的动物模型，包括症状 由心理压力引起的急性发作。我们的实验室是独一无二的， 几个相关的模型，以加强我们的研究，包括（例如，环磷酰胺（CTX）诱导的膀胱炎， 慢性、尿路上皮过度表达NGF（NGF-OE）的转基因小鼠，重复、低剂量的顺铂（单独 不足以产生显著的症状）加上重复变量压力（RVS），以评估压力如何 会加重疾病。我们的总体假设是，尿频和盆腔感觉的增加， 伴随的BPS/IC反映了神经化学介质的表达、功能和相互作用的增加， 感觉换能器，TRPV 4，在排尿反射的感觉成分，有利于前兴奋性 状态基于我们以前的工作，NGF/TrkA/p75 NTR信号转导和下游的适应不良作用（S） 排尿反射感觉成分中TRPV 4/Ca 2+的激活将被评估为促成 BPS/IC机制。目的1：确定中断NGF/TrkA/p75 NTR信号通路是否会减少排尿 频率和盆腔疼痛：减少（1）尿路上皮Ca 2+事件;（2）尿路上皮ATP释放和（3）膀胱 传入活动进一步中断NGF/p75 NTR信号传导通过以下方式降低排尿频率：（1）降低排尿频率， 尿路上皮细胞凋亡;（2）促进尿路上皮细胞修复;（3）维持跨上皮阻力。 目的2：确定排尿通路中NGF信号传导的中断是否具有短期和长期的作用。 对BPS/IC样症状中TRPV 4/Ca 2+功能的影响。急性NGF介导的TRPV 4/Ca 2 + BPS/IC相关的反应包括增加的尿路上皮Ca 2+信号传导、尿路上皮ATP分泌和膀胱炎。 传入神经活动适应不良的长期NGF信号通过增加TRPV 4转录促进BPS/IC 和蛋白质表达。使用三种具有BPS/IC样症状的模型和多学科的细胞-组织- 系统实验的方法，我们将确定：（1）潜在的结构和功能的变化 心理应激对膀胱功能和疼痛的影响 （3）新的治疗方法。