Cystitis-Induced Plasticity of Micturitin Reflexes
膀胱炎引起的尿素反射可塑性
基本信息
- 批准号:8508379
- 负责人:
- 金额:$ 45.76万
- 依托单位:
- 依托单位国家:美国
- 项目类别:
- 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:
- 关键词:AddressAdverse effectsAffectAfferent PathwaysAgonistAntibodiesBehaviorBiochemicalBladderC FiberCellsChronicClinical TrialsConfocal MicroscopyConsciousCystitisCytokeratinDyesEconomic BurdenEnrollmentEsthesiaExhibitsFamily memberFiberFrequenciesFundingGrantGrowth Factor OverexpressionHypersensitivityImmunohistochemistryIn Situ HybridizationIncreased frequency of micturitionInflammatoryInositolInterstitial CystitisIon ChannelLabelLifeLimb structureMeasurementMediatingMediator of activation proteinMethodologyMicturition ReflexMolecularMonoclonal AntibodiesMusNerve Growth FactorsNeuropeptidesPACAPR-1 proteinPainPain DisorderPathway interactionsPatientsPelvic PainPelvisPerceptionPeripheral NervesPhospholipase CPolymerase Chain ReactionPreparationProductionProteinsQuality of lifeReflex actionResearch ProposalsRouteSecondary toSensorySensory PhysiologySignal TransductionSpecificitySpinal GangliaSymptomsSyndromeTestingTherapeuticTimeTissuesTranscriptTransducersTransgenic MiceUPK2 geneUp-RegulationUrinationUrothelial CellUrotheliumVisceralWestern BlottingWorkbasechronic painchronic pelvic paindesignimprovedinsect maxadilan proteininsightinterdisciplinary approachintravesicalirritationmouse modelneurochemistryneurofilament protein Hnoveloverexpressionpatch clampperipherinpituitary adenylate cyclase activating polypeptidepituitary adenylate cyclase-activating peptide receptorpressurepromoterpublic health relevancereceptorresearch studyresponsetripolyphosphateurinaryurinary bladder hyperreflexia
项目摘要
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,其特征是疼痛,压力或不适感被认为是至少与一种尿症状相关的膀胱。 BPS/IC对生活质量和经济负担的影响是巨大的。在这笔赠款的生活中,我们假设与BPS/IC相关的疼痛涉及内脏感觉/膀胱感官生理的改变。内脏感觉的变化可能部分是通过包括神经生长因子(NGF)的尿膀胱变化来介导的。 BPS/IC患者专门抑制NGF的单克隆抗体治疗证明了概念证明。但是,由于严重的副作用,临床试验已停止入学率。 NGF以外的其他目标的需求很明显。通过这种竞争性更新的应用,我们提出了目标,该目标将提供机械洞察力,以在慢性NGF过表达(NGF-OEE)的新型转基因小鼠模型中使用尿素尿素II的促进剂进行促进,从而在新型的慢性NGF过表达(NGF-OEE)的新型转基因小鼠模型中有助于膀胱过度反射和骨盆超敏反应,以促进效果促进效果。工作假设是,伴随BPS/IC的尿频和改变的增加是由于神经化学介体的表达,功能和相互作用的改变引起的,在尿液Bladder反射的感觉肢中,神经化学介体的表达,功能和相互作用,感官传感器,瞬态受体电位(TRPV)家族成员TRPV4。这些研究检查了NGF-OE小鼠中神经肽,PACAP和受体PAC1和TRPV4对增加空隙频率和体细胞敏感性的贡献和相互作用。目的1:我们假设NGF过表达在NGF-OE小鼠模型的尿路上皮和腰椎背根神经节(DRG)中诱导感觉传感器TRPV4,在DRG和尿道膀胱尿道细胞中的膀胱传感细胞中的感觉传感器的上调。我们假设在NGF-OEE小鼠中,TRPV4的组织特异性表达,在尿液反射的感觉成分(尿皮上,DRG)中有助于膀胱膀胱过度反射和骨盆超敏。 AIM 2:我们假设TRPV4与PACAP/PAC1之间的相互作用可能代表了一种新型机制,PACAP/PAC1信号传导激活磷脂酶C和三磷酸肌醇,以使TRPV4介导的空隙行为和痛苦感觉的变化敏感。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。我们将使用一种多学科方法,包括解剖学,生化,分子,电生理和功能方法论以及一种新型的离体外周神经记录方法来解决这些目标。结果将提供对具有治疗潜力的新目标的关键见解,以改善膀胱功能和内脏感觉。
项目成果
期刊论文数量(0)
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MARGARET Ann VIZZARD其他文献
MARGARET Ann VIZZARD的其他文献
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{{ truncateString('MARGARET Ann VIZZARD', 18)}}的其他基金
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 - 财政年份:2021
- 资助金额:
$ 45.76万 - 项目类别:
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 - 财政年份:2021
- 资助金额:
$ 45.76万 - 项目类别:
Role of proNGF-p75 signaling in the bladder control after spinal cord injury
proNGF-p75 信号在脊髓损伤后膀胱控制中的作用
- 批准号:
10360573 - 财政年份:2019
- 资助金额:
$ 45.76万 - 项目类别:
Role of proNGF-p75 signaling in the bladder control after spinal cord injury
proNGF-p75 信号在脊髓损伤后膀胱控制中的作用
- 批准号:
10604309 - 财政年份:2019
- 资助金额:
$ 45.76万 - 项目类别:
Cystitis-Induced Plasticity of Micturition Reflexes
膀胱炎引起的排尿反射可塑性
- 批准号:
8011784 - 财政年份:2010
- 资助金额:
$ 45.76万 - 项目类别:
Neurotrophic Mechanisms in LUT Plasticity with Cystitis
膀胱炎 LUT 可塑性的神经营养机制
- 批准号:
7108522 - 财政年份:2003
- 资助金额:
$ 45.76万 - 项目类别:
Neurotrophic Mechanisms in LUT Plasticity with Cystitis
膀胱炎 LUT 可塑性的神经营养机制
- 批准号:
6932294 - 财政年份:2003
- 资助金额:
$ 45.76万 - 项目类别:
Neurotrophic Mechanisms in LUT Plasticity with Cystitis
膀胱炎 LUT 可塑性的神经营养机制
- 批准号:
7278299 - 财政年份:2003
- 资助金额:
$ 45.76万 - 项目类别:
Neurotrophic Mechanisms in LUT Plasticity with Cystitis
膀胱炎 LUT 可塑性的神经营养机制
- 批准号:
6709614 - 财政年份:2003
- 资助金额:
$ 45.76万 - 项目类别:
Neurotrophic Mechanisms in LUT Plasticity with Cystitis
膀胱炎 LUT 可塑性的神经营养机制
- 批准号:
6803515 - 财政年份:2003
- 资助金额:
$ 45.76万 - 项目类别:
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