Central Sites of Action for Bladder Neuromodulation

描述（由申请方提供）：膀胱过度活动症（OAB）和间质性膀胱炎/膀胱疼痛综合征（IC/BPS）是病理和病因未知的疾病。OAB和IC/BPS对生活质量具有破坏性的心理和社会影响，但这些疾病的治疗在临床上具有挑战性。骶神经调节是FDA批准的OAB治疗方法。目前，它只提供给药物治疗失败后的OAB患者。自FDA批准OAB以来，骶神经调节在许多临床试验中已被证明可有效治疗IC/BPS，目前已被列入IC/BPS的AUA指南中，作为建议的治疗选择之一。此外，临床研究表明阴部神经调节上级骶神经调节。它成功治疗了骶神经调节失败的OAB或IC/BPS患者。此外，最近的多中心临床试验表明，胫神经调节治疗OAB有效。虽然神经调节是OAB或IC/BPS的有效治疗方法，但神经调节（骶骨、阴部或胫骨）的机制仍不清楚。更令人惊讶的是，在基础科学研究中，旨在揭示神经调节的作用机制的努力非常有限。在这个项目中，我们建议通过回答以下问题来确定神经调节作用的中心位点：1。神经调节作用于脊髓还是大脑2.它是否作用于由膀胱A？纤维传入激活的脊髓延髓排尿反射通路的上行或下行分支，或作用于由有害的C纤维膀胱传入激活的脊髓排尿反射通路？3.哪些神经递质参与神经调节？4.神经调节如何改变与膀胱伤害感受/过度活动相关的大脑感觉和运动活动？将研究并比较不同的神经调节方法（骶骨、阴部或胫骨）以回答这些问题。确定不同神经调节疗法的作用部位必将指导临床医生和患者选择最佳治疗策略，从而显著改善治疗OAB或IC/BPS的临床结局。有关作用部位和神经调节基础的神经递质机制的信息也可能有助于开发治疗OAB或IC/BPS的新药。我们的研究将使数百万患有OAB或IC/BPS的美国人受益匪浅。

DESCRIPTION (provided by applicant): Overactive bladder (OAB) and interstitial cystitis/bladder pain syndrome (IC/BPS) are diseases with unknown pathology and etiology. OAB and IC/BPS have devastating psychological and social impacts on quality of life, but treatments for these diseases are clinically challenging. Sacral neuromodulation is a FDA approved treatment for OAB. Currently it is only offered to OAB patients after pharmacotherapy has failed. Since its FDA approval for OAB, sacral neuromodulation has been shown to be effective in treating IC/BPS in many clinical trials and is currently listed in the AUA guideline o IC/BPS as one of the suggested treatment options. In addition clinical studies have showed that pudendal neuromodulation is superior to sacral neuromodulation. It successfully treated OAB or IC/BPS patients who have failed sacral neuromodulation. Furthermore, recent multicenter clinical trials have indicated that tibial neuromodulation is effective for treatment of OAB. Although neuromodulation is an effective treatment for OAB or IC/BPS, the mechanism underlying neuromodulation (sacral, pudendal, or tibial) is still unknown. More surprisingly there is very limited effort in basic science research aimed at revealing the mechanism of action underlying neuromdulation. In this project we propose to determine the central sites of action for neuromodulation by answering the following questions: 1. whether neuromodulation acts in the spinal cord or in the brain? 2. Whether it acts on the ascending or descending limbs of the spinobulbospinal micturition reflex pathway activated by bladder A¿-fiber afferents or on the spinal micturition reflex pathway activated by noxious C-fiber bladder afferents? 3. What neurotransmitters are involved in neuromodulation? 4. How brain sensory and motor activity associated with bladder nociception/overactivity is altered by neuromodulation? Different neuromodulation methods (sacral, pudendal, or tibial) will be investigated and compared to answer these questions. Identifying the sites of action for different neuromodulation therapies will surely guide clinicians and patients in selection of the optimal treatment strategies and thereby significantly improve the clinical outcomes in treating OAB or IC/BPS. Information about the sites of action and the neurotransmitter mechanisms underlying neuromodulation could also be useful in developing new drugs to treat OAB or IC/BPS. Our studies will significantly benefit millions of Americans suffering from OAB or IC/BPS.