Pharmacology of Intravesical Antisense Based Therapy for Over Active Bladder
膀胱内反义疗法治疗膀胱过度活动症的药理学
基本信息
- 批准号:8528570
- 负责人:
- 金额:$ 30.49万
- 依托单位:
- 依托单位国家:美国
- 项目类别:
- 财政年份:2011
- 资助国家:美国
- 起止时间:2011-09-01 至 2015-07-31
- 项目状态:已结题
- 来源:
- 关键词:AcetylcholineAdverse effectsAfferent NeuronsAfferent PathwaysAnimal ModelAnimalsAnti-CholinergicsAntibodiesApplications GrantsArthralgiaAttenuatedBiotechnologyBladderBladder UrotheliumC FiberCellsChronicConstipationCorneal NeovascularizationDevelopmentDouble-Blind MethodDrug DesignDrug TargetingEyedropsFoundationsFutureGene SilencingGenesGrowth FactorGrowth Factor GeneGrowth Factor InhibitionHumanHypesthesiaIncreased frequency of micturitionInflammatoryInflammatory ResponseInjection of therapeutic agentInterventionIntravesical InstillationIon ChannelLabelLeadLiposomesMediatingMethodsMicturition ReflexModalityModelingMolecularMuscarinic Acetylcholine ReceptorMuscarinic AntagonistsMuscarinicsNerve Growth Factor 1Nerve Growth FactorsNeuropeptidesOveractive BladderParesthesiaPathologyPatientsPharmaceutical PreparationsPharmacologic SubstancePharmacologyPhysiologicalPotassium ChannelProductionProstaglandinsPumpQuality of lifeRattusReceptor GeneRefractoryReportingResearchRiskRouteSafetySignal PathwaySiteSodium ChannelSpinal cord injuryStretchingSymptomsTRPV1 geneTechniquesTechnologyTestingTherapeutic AgentsTherapeutic EffectUniversity HospitalsUp-RegulationUrineUrotheliumWestern BlottingXerostomiabasecholinergiccomparative efficacycytokineinnovationinterestintravesicalirritationlaser capture microdissectionlower urinary tract symptomsmRNA Expressionnovelnovel therapeutic interventionnovel therapeuticspatch clampprogramsprospectiveprotein expressionresearch studytherapeutic targettherapy designtreatment strategyvoltage
项目摘要
DESCRIPTION: Because of current, limited options for treating overactive bladder (OAB) or lower urinary tract symptoms (LUTS), there is a great demand for the development of new treatment strategy. In this application, the following key aims utilize unique and innovative expertise, available at William Beaumont Hospital and University of Pittsburgh to develop new therapeutic options for OAB and detrusor overactivity (DO) by especially targeting bladder afferent hyperexcitability, which has been proposed as one of the important mechanisms underlying OAB, using rats with spinal cord injury (SCI). Sequence-specific gene-silencing mechanism is a promising approach for developing therapeutics agent based on rational gene-based drug design. In the current proposal, we propose to use this approach for silencing nerve growth factor (NGF) gene locally in the bladder. Local inhibition of NGF gene in bladder akin to antisense eye drops for corneal angiogenesis can avoid the safety concerns noted with systemic anti-NGF therapy from monoclonal human NGF antibodies (tanezumab) such as paresthesia, hypoesthesia and arthralgia. By comparing the pharmacology of NGF antisense administered via different routes, we propose to investigate the contribution of NGF derived from urothelium on afferent hyperexcitability leading to DO in SCI animals. Secondly, we will also test the hypothesis of OAB pathology triggered by changes in voltage- gated sodium and potassium channels, increased cytokines expression/release as well as muscarinic receptors, and such changes are mediated by excessive NGF expression in bladder. The proposed experiments will use antisense to elucidate whether NGF inhibition could normalize changes in muscarinic and ion channel mechanisms contributing to afferent hyperexcitability resulting in DO/OAB. We will study the changes in the local muscarinic cholinergic mechanism underlying DO, including altered sensitivity to various antimuscarinic agents. This mechanism is important to investigate because there is increasing evidence that non-neural acetylcholine (ACh) released from the urothelium during stretch can activate muscarinic receptors, leading to modulation of afferent pathways during the micturition reflex, and that increased ACh levels in the bladder can induce OAB mediated by the local effects on muscarinic receptors in the urothelium/suburothelium. The long-term objectives of the research program are to establish new and effective therapeutic targets and/or interventions strategies for the treatment of OAB.
产品说明:由于目前治疗膀胱过度活动症(OAB)或下尿路症状(LUTS)的选择有限,因此迫切需要开发新的治疗策略。在本申请中,以下关键目标利用William博蒙医院和匹兹堡大学的独特和创新专业知识,通过特别针对膀胱传入过度兴奋(已被提出为脊髓损伤(SCI)大鼠OAB的重要机制之一),开发OAB和逼尿肌过度活动(DO)的新治疗选择。序列特异性基因沉默机制是基于合理基因药物设计开发治疗药物的一条有前途的途径。在目前的建议中,我们建议使用这种方法沉默神经生长因子(NGF)基因在膀胱局部。类似于用于角膜血管生成的反义滴眼液,在膀胱中局部抑制NGF基因可以避免使用单克隆人NGF抗体(tanezumab)的全身性抗NGF治疗所注意到的安全性问题,例如感觉异常、感觉减退和关节痛。通过比较通过不同途径给予的NGF反义的药理学,我们建议调查来自尿道的NGF对SCI动物中导致DO的传入过度兴奋的贡献。其次,我们还将检验由电压门控钠和钾通道的变化、增加的细胞因子表达/释放以及毒蕈碱受体触发的OAB病理学的假设,并且这种变化由膀胱中过度的NGF表达介导。拟议的实验将使用反义来阐明NGF抑制是否可以使导致DO/OAB的传入超兴奋性的毒蕈碱和离子通道机制的变化正常化。我们将研究局部毒蕈碱胆碱能机制的变化,包括对各种抗毒蕈碱剂的敏感性改变。这种机制是重要的调查,因为有越来越多的证据表明,非神经乙酰胆碱(ACh)释放的尿路刺激在拉伸过程中可以激活毒蕈碱受体,导致在排尿反射过程中的传入通路的调制,并在膀胱中增加ACh水平可以诱导OAB介导的局部作用对毒蕈碱受体的尿路刺激/亚尿路刺激。该研究项目的长期目标是建立新的有效的治疗OAB的治疗靶点和/或干预策略。
项目成果
期刊论文数量(0)
专著数量(0)
科研奖励数量(0)
会议论文数量(0)
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MICHAEL B CHANCELLOR其他文献
MICHAEL B CHANCELLOR的其他文献
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{{ truncateString('MICHAEL B CHANCELLOR', 18)}}的其他基金
Michigan Interdisciplinary Center for Urology Research and Education (MI-CURE)
密歇根泌尿外科研究和教育跨学科中心 (MI-CURE)
- 批准号:
10491200 - 财政年份:2021
- 资助金额:
$ 30.49万 - 项目类别:
Michigan Interdisciplinary Center for Urology Research and Education (MI-CURE)
密歇根泌尿外科研究和教育跨学科中心 (MI-CURE)
- 批准号:
10375149 - 财政年份:2021
- 资助金额:
$ 30.49万 - 项目类别:
Pharmacology of Intravesical Antisense Based Therapy for Over Active Bladder
膀胱内反义疗法治疗膀胱过度活动症的药理学
- 批准号:
8432297 - 财政年份:2011
- 资助金额:
$ 30.49万 - 项目类别:
Pharmacology of Intravesical Antisense Based Therapy for Over Active Bladder
膀胱内反义疗法治疗膀胱过度活动症的药理学
- 批准号:
8103682 - 财政年份:2011
- 资助金额:
$ 30.49万 - 项目类别:
Pharmacology of Intravesical Antisense Based Therapy for Over Active Bladder
膀胱内反义疗法治疗膀胱过度活动症的药理学
- 批准号:
8322516 - 财政年份:2011
- 资助金额:
$ 30.49万 - 项目类别:
Pharmacology of Intravesical Antisense Based Therapy for Over Active Bladder
膀胱内反义疗法治疗膀胱过度活动症的药理学
- 批准号:
8706852 - 财政年份:2011
- 资助金额:
$ 30.49万 - 项目类别:
Intravesical liposome drug delivery to treat interstitial cystitis
膀胱内脂质体给药治疗间质性膀胱炎
- 批准号:
8088108 - 财政年份:2010
- 资助金额:
$ 30.49万 - 项目类别:
Intravesical liposome drug delivery to treat interstitial cystitis
膀胱内脂质体给药治疗间质性膀胱炎
- 批准号:
8293399 - 财政年份:2010
- 资助金额:
$ 30.49万 - 项目类别:
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