Cystitis-induced bladder dysfunction and pain

膀胱炎引起的膀胱功能障碍和疼痛

• 批准号: 10545170
• 负责人: MARGARET Ann VIZZARD
• 金额: $ 48.69万
• 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/10545170
• 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; Micturition Reflex; Modeling; Mus; NGFR Protein; Pain; Pain Disorder; Pathway interactions; Patients; Pelvic Pain; Pelvis; Psychological Stress; Publishing; Quality of life; Recovery; Research; Resistance; Role; Sensory; Signal Pathway; Signal Transduction; Signs and Symptoms; Spinal Ganglia; Spinal cord injury; Stress; 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; improved; innovation; insight; interdisciplinary approach; member; mouse model; multidisciplinary; neurochemistry; novel; overexpression; pain perception; pharmacologic; 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/文摘