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：
8706852
负责人：
MICHAEL B CHANCELLOR
金额：
$ 30.88万
依托单位：
UNIVERSITY OF PITTSBURGH AT PITTSBURGH
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 2016-07-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8706852
关键词：
Acetylcholine Adverse effects Afferent Neurons Afferent Pathways Animal Model Animals Anti-Cholinergics Antibodies Applications Grants Arthralgia Attenuated Biotechnology Bladder Bladder Urothelium C Fiber Cells Chronic Constipation Corneal Neovascularization Development Double-Blind Method Drug Design Drug Targeting Eyedrops Foundations Future Gene Silencing Genes Growth Factor Growth Factor Gene Growth Factor Inhibition Human Hypesthesia Increased frequency of micturition Inflammatory Inflammatory Response Injection of therapeutic agent Intervention Intravesical Instillation Ion Channel Label Lead Liposomes Mediating Methods Micturition Reflex Modality Modeling Molecular Muscarinic Acetylcholine Receptor Muscarinic Antagonists Muscarinics Nerve Growth Factor 1 Nerve Growth Factors Neuropeptides Overactive Bladder Paresthesia Pathology Patients Pharmaceutical Preparations Pharmacologic Substance Pharmacology Physiological Potassium Channel Production Prostaglandins Pump Quality of life Rattus Receptor Gene Refractory Reporting Research Risk Route Safety Signal Pathway Site Sodium Channel Spinal cord injury Stretching Symptoms TRPV1 gene Techniques Technology Testing Therapeutic Agents Therapeutic Effect University Hospitals Up-Regulation Urine Urothelium Western Blotting Xerostomia base cholinergic comparative efficacy cytokine innovation interest intravesical irritation laser capture microdissection lower urinary tract symptoms mRNA Expression novel novel therapeutic intervention novel therapeutics patch clamp programs prospective protein expression research study therapeutic target therapy design treatment strategy voltage

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.

描述：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。在此应用中，以下关键目标利用威廉博蒙特医院和匹兹堡大学提供的独特和创新的专业知识，通过特别针对膀胱传入过度兴奋性来开发针对 OAB 和逼尿肌过度活动 (DO) 的新治疗方案，膀胱传入过度兴奋性已被提议为使用脊髓损伤 (SCI) 大鼠研究 OAB 的重要机制。序列特异性基因沉默机制是基于合理的基因药物设计开发治疗剂的一种有前途的方法。在当前的提案中，我们建议使用这种方法来沉默膀胱局部的神经生长因子（NGF）基因。类似于用于角膜血管生成的反义滴眼液，局部抑制膀胱中的 NGF 基因可以避免单克隆人 NGF 抗体（tanezumab）全身性抗 NGF 治疗所引起的安全问题，例如感觉异常、感觉减退和关节痛。通过比较通过不同途径施用的 NGF 反义药的药理学，我们建议研究源自尿路上皮的 NGF 对导致 SCI 动物 DO 的传入过度兴奋的贡献。其次，我们还将测试由电压门控钠和钾通道的变化、细胞因子表达/释放增加以及毒蕈碱受体的变化引发的OAB病理学假设，并且这种变化是由膀胱中过度的NGF表达介导的。拟议的实验将使用反义来阐明 NGF 抑制是否可以使毒蕈碱和离子通道机制的变化正常化，从而导致传入过度兴奋，从而导致 DO/OAB。我们将研究 DO 潜在的局部毒蕈碱胆碱能机制的变化，包括对各种抗毒蕈碱药物的敏感性改变。这种机制的研究很重要，因为越来越多的证据表明，在拉伸过程中从尿路上皮释放的非神经性乙酰胆碱 (ACh) 可以激活毒蕈碱受体，导致排尿反射期间传入通路的调节，并且膀胱中 ACh 水平的增加可以通过对尿路上皮/尿路上皮下毒蕈碱受体的局部作用介导 OAB。该研究计划的长期目标是为 OAB 的治疗建立新的有效治疗靶点和/或干预策略。

项目成果

期刊论文数量（18）

专著数量（0）

科研奖励数量（0）

会议论文数量（0）

专利数量（0）

Effects of herpes simplex virus vectors encoding poreless TRPV1 or protein phosphatase 1α in a rat cystitis model induced by hydrogen peroxide.

单纯疱疹病毒载体编码无孔 TRPV1 或蛋白磷酸酶 1α 在过氧化氢诱导的大鼠膀胱炎模型中的影响。

DOI：
发表时间：
2018-01
期刊：
影响因子：
5.1
作者：
Takai, S;Majima, T;Reinhart, B;Goins, W F;Funahashi, Y;Gotoh, M;Tyagi, P;Glorioso, J C;Yoshimura, N
通讯作者：
Yoshimura, N

Differential contribution of Kv4-containing channels to A-type, voltage-gated potassium currents in somatic and visceral dorsal root ganglion neurons.

含 Kv4 的通道对体细胞和内脏背根神经节神经元中 A 型电压门控钾电流的差异贡献。

DOI：
发表时间：
2014-11-15
期刊：
影响因子：
2.5
作者：
Yunoki, Takakazu;Takimoto, Koichi;Kita, Kaori;Funahashi, Yasuhito;Takahashi, Ryosuke;Matsuyoshi, Hiroko;Naito, Seiji;Yoshimura, Naoki
通讯作者：
Yoshimura, Naoki

压力相关肽铃蟾肽通过脑铃蟾肽受体 1 型和 2 型集中诱导大鼠频繁排尿。

DOI：
发表时间：
2016-03
期刊：
影响因子：
0
作者：
Shimizu, Takahiro;Shimizu, Shogo;Higashi, Youichirou;Nakamura, Kumiko;Yoshimura, Naoki;Saito, Motoaki
通讯作者：
Saito, Motoaki

Urinary chemokines as noninvasive predictors of ulcerative interstitial cystitis.

尿趋化因子作为溃疡性间质性膀胱炎的非侵入性预测因子。

DOI：
发表时间：
2012-06
期刊：
影响因子：
0
作者：
Tyagi, Pradeep;Killinger, Kim;Tyagi, Vikas;Nirmal, Jayabalan;Chancellor, Michael;Peters, Kenneth M
通讯作者：
Peters, Kenneth M

Roles of adenosine A1 and A2A receptors in the control of micturition in rats.

腺苷 A1 和 A2A 受体在控制大鼠排尿中的作用。

DOI：
发表时间：
2014-11
期刊：
影响因子：
2
作者：
Kitta, Takeya;Chancellor, Michael B;de Groat, William C;Kuno, Sadako;Nonomura, Katsuya;Yoshimura, Naoki
通讯作者：
Yoshimura, Naoki