Cystitis-Induced Plasticity of Micturitin Reflexes

膀胱炎引起的尿素反射可塑性

• 批准号: 8642172
• 负责人: MARGARET Ann VIZZARD
• 金额: $ 47.07万
• 依托单位: UNIVERSITY OF VERMONT & ST AGRIC COLLEGE
• 依托单位国家: 美国
• 财政年份: 1996
• 资助国家: 美国
• 起止时间: 1996-07-29 至 2018-05-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8642172
• 关键词: Address; Adverse effects; Affect; Afferent Pathways; Agonist; Antibodies; Behavior; Biochemical; Bladder; C Fiber; Cells; Chronic; Clinical Trials; Confocal Microscopy; Conscious; Cystitis; Cytokeratin; Dyes; Economic Burden; Enrollment; Esthesia; Exhibits; Family member; Fiber; Frequencies; Funding; Grant; Growth Factor Overexpression; Hypersensitivity; Immunohistochemistry; In Situ Hybridization; Increased frequency of micturition; Inflammatory; Inositol; Interstitial Cystitis; Ion Channel; Label; Life; Limb structure; Measurement; Mediating; Mediator of activation protein; Methodology; Micturition Reflex; Molecular; Monoclonal Antibodies; Mus; Nerve Growth Factors; Neuropeptides; PACAPR-1 protein; Pain; Pain Disorder; Pathway interactions; Patients; Pelvic Pain; Pelvis; Perception; Peripheral Nerves; Phospholipase C; Polymerase Chain Reaction; Preparation; Production; Proteins; Quality of life; Reflex action; Research Proposals; Route; Secondary to; Sensory; Sensory Physiology; Signal Transduction; Specificity; Spinal Ganglia; Symptoms; Syndrome; Testing; Therapeutic; Time; Tissues; Transcript; Transducers; Transgenic Mice; UPK2 gene; Up-Regulation; Urination; Urothelial Cell; Urothelium; Visceral; Western Blotting; Work; base; chronic pain; chronic pelvic pain; design; improved; insect maxadilan protein; insight; interdisciplinary approach; intravesical; irritation; mouse model; neurochemistry; neurofilament protein H; novel; overexpression; patch clamp; peripherin; pituitary adenylate cyclase activating polypeptide; pituitary adenylate cyclase-activating peptide receptor; pressure; promoter; public health relevance; receptor; research study; response; tripolyphosphate; urinary; urinary bladder hyperreflexia

DESCRIPTION (provided by applicant): Bladder pain syndrome (BPS)/interstitial cystitis (IC) is a chronic pain syndrome characterized by pain, pressure or discomfort perceived to be bladder related with at least one urinary symptom. The impact of BPS/IC on quality of life and economic burden are enormous. Over the life of this grant, we have hypothesized that pain associated with BPS/IC involves an alteration of visceral sensation/bladder sensory physiology. Changes in visceral sensation may be mediated, in part, by inflammatory changes in the urinary bladder including nerve growth factor (NGF). Monoclonal antibody treatment that specifically inhibits NGF in patients with BPS/IC demonstrates proof of concept; however, clinical trials have halted enrollment due to severe side effects. The need for additional targets beyond NGF is clear. With this competitive renewal application, we propose aims that will provide mechanistic insight into additional NGF-mediated pleiotropic changes that contribute to urinary bladder hyperreflexia and pelvic hypersensitivity in a novel transgenic mouse model of chronic NGF overexpression (NGF-OE) using the urothelium-specific uroplakin II promoter that was characterized during the last funding cycle. The working hypothesis is that increases in urinary frequency and altered sensation that accompany BPS/IC are due to an alteration in the expression, function and interactions of neurochemical mediators and the sensory transducer, transient receptor potential (TRPV) family member TRPV4, in the sensory limb of the urinary bladder reflex. These studies examine the contributions of and interactions between the neuropeptide, PACAP, and receptor PAC1 and TRPV4 to increased voiding frequency and somatic sensitivity in NGF-OE mice. Aim 1: We hypothesize that NGF overexpression exhibited in urothelium and lumbosacral dorsal root ganglia (DRG) of the NGF-OE mouse model induces upregulation of the sensory transducer, TRPV4, in bladder afferent cells in DRG and in urothelial cells of the urinary bladder. We hypothesize that tissue-specific expression of TRPV4, in sensory components (urothelium, DRG) of the micturition reflex contributes to urinary bladder hyperreflexia and pelvic hypersensitivity in NGF-OE mice. Aim 2: We hypothesize that interactions between TRPV4 and PACAP/PAC1 may represent a novel mechanism by which PACAP/PAC1 signaling activates phospholipase C and inositol triphosphate to sensitize TRPV4-mediated changes in voiding behavior and painful sensation. Furthermore, we hypothesize that PAC1 and TRPV4 are co-expressed in bladder afferent DRG and urothelial cells. We will use a multidisciplinary approach including anatomical, biochemical, molecular, electrophysiological, and functional methodologies and a novel ex vivo peripheral nerve recording approach to address these aims. Results will provide key insights into new targets with therapeutic potential to improve urinary bladder function and visceral sensation.

描述（由申请人提供）：膀胱疼痛综合征（BPS）/间质性膀胱炎（IC）是一种慢性疼痛综合征，其特征是被认为与膀胱相关的疼痛、压力或不适，并与至少一种泌尿系统症状相关。 BPS/IC 对生活质量和经济负担的影响是巨大的。在这笔资助的整个生命周期中，我们假设与 BPS/IC 相关的疼痛涉及内脏感觉/膀胱感觉生理学的改变。内脏感觉的变化可能部分是由膀胱中的炎症变化（包括神经生长因子（NGF））介导的。特异性抑制 BPS/IC 患者 NGF 的单克隆抗体治疗证明了概念；然而，由于严重的副作用，临床试验已停止招募。显然需要 NGF 之外的其他目标。通过这一竞争性更新申请，我们提出的目标是，使用上一个资助周期中表征的尿路上皮特异性尿斑蛋白 II 启动子，为慢性 NGF 过度表达 (NGF-OE) 的新型转基因小鼠模型中导致膀胱反射亢进和盆腔过敏的额外 NGF 介导的多效性变化提供机制见解。目前的假设是，伴随 BPS/IC 的尿频增加和感觉改变是由于膀胱反射感觉肢中神经化学介质和感觉传感器、瞬时受体电位 (TRPV) 家族成员 TRPV4 的表达、功能和相互作用的改变所致。这些研究考察了神经肽 PACAP 以及受体 PAC1 和 TRPV4 对 NGF-OE 小鼠排尿频率和躯体敏感性增加的贡献和相互作用。目标 1：我们假设 NGF-OE 小鼠模型的尿路上皮和腰骶背根神经节 (DRG) 中表现出的 NGF 过表达会诱导 DRG 中的膀胱传入细胞和膀胱尿路上皮细胞中的感觉传感器 TRPV4 上调。我们假设排尿反射的感觉成分（尿路上皮，DRG）中 TRPV4 的组织特异性表达导致 NGF-OE 小鼠的膀胱反射亢进和盆腔过敏。目标 2：我们假设 TRPV4 和 PACAP/PAC1 之间的相互作用可能代表一种新机制，PACAP/PAC1 信号通过该机制激活磷脂酶 C 和三磷酸肌醇，从而使 TRPV4 介导的排尿行为和疼痛感觉变化变得敏感。此外，我们假设 PAC1 和 TRPV4 在膀胱传入 DRG 和尿路上皮细胞中共表达。我们将使用多学科方法，包括解剖学、生化、分子、电生理学和功能方法以及新颖的离体周围神经记录方法来实现这些目标。结果将为具有改善膀胱功能和内脏感觉的治疗潜力的新靶标提供重要见解。