Closed Loop Wireless Monitoring and Optogenetic Modulation of Bladder Function

膀胱功能的闭环无线监测和光遗传学调制

• 批准号: 9519550
• 负责人: Aaron David Mickle
• 金额: $ 6.12万
• 依托单位: WASHINGTON UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2017
• 资助国家: 美国
• 起止时间: 2017-07-01 至 2019-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9519550
• 关键词: Abdomen; Address; Afferent Neurons; Algorithms; Animal Model; Animals; Attenuated; Biological Assay; Bladder; Bladder Control; Bladder Dysfunction; Bluetooth; Catheterization; Catheters; Collaborations; Cyclophosphamide; Cystitis; Data; Development; Devices; Disadvantaged; Disease; Electrodes; Exposure to; Frequencies; Functional disorder; Future; G-Protein-Coupled Receptors; Geometry; Goals; HSV vector; Hyperactive behavior; Hypersensitivity; Inflammation; Interstitial Cystitis; Intervention; Ion Channel; Laboratories; Lead; Left; Light; Measurement; Measures; Methods; Modeling; Molecular Target; Monitor; Nerve; Neurons; Nociception; Opsin; Overactive Bladder; Pain; Pathology; Patients; Pelvis; Physiology; Population; Proton Pump; Pump; Rattus; Regulation; Resistance; Role; Scientist; Sensory; System; Tablets; Techniques; Technology; Testing; Therapeutic; Time; Transgenic Mice; Translating; Translations; United States; Viral; Viral Vector; Virus Activation; Wireless Technology; awake; base; bladder pain; clinically translatable; design; experimental study; implantable device; implantation; ineffective therapies; innovation; insight; new technology; novel; novel therapeutics; optogenetics; preference; pressure; programs; response

ABSTRACT Millions of people in the United States suffer from bladder dysfunction and pain caused by interstitial cystitis/bladder pain syndrome and overactive bladder. The underling pathologies for many of these diseases are poorly understood and this is the primary reason why most current treatments are ineffective. To address this issue, our group has designed and tested an implantable wireless optoelectronic system to monitor and modulate bladder function. Our hyper-conformal strain gauge wraps around the bladder and as the bladder expands, changes in geometry of the device linearly increases resistance which can then be directly correlated with bladder size or fullness. We have attached microscale light emitting diodes (μLED) to the strain gauge that can be used to activate light-sensitive opsins for optogenetic regulation of neuronal activity. The strain gauge and μLEDs connect to an implantable base station that allows for wireless control and monitoring of bladder activity. This new technology eliminates the need for implantation of potentially-damaging bladder catheters or electrodes, and provides unique access to bladder functionality in the awake, freely-moving rat. I plan to utilize viral delivery of opsins and a novel strain gauge that measures dynamic changes in bladder circumference, to modulate and monitor bladder function, respectively. My preliminary data show that changes in strain gauge resistance correlates to traditional bladder activity measurements like intravesicular pressure, and that virally delivered inhibitory opsin, Archaerhodopsin (Arch), can delay bladder contractions in anesthetized rats. I plan to test the ability of virally transduced Arch expressed in bladder afferents to reduce frequency and increase voiding volume after cyclophosphamide (CYP) -induced cystitis in awake animals (Aim 1a and b). I also plan to use our newly developed wireless technology to implement a closed-loop system that can recognize increased frequency of bladder contractions and initiate optogenetic inhibition to normalize voiding (Aim 1c). Bladder pain is the most common complaint of patients suffering from IC/BPS. Using our wireless μLED strain gauge, I plan to determine whether activation of activation of virally transduced Arch, in bladder afferents, is sufficient to attenuate bladder hypersensitivity in rats with CYP-induced cystitis. This sensitivity will be assayed by visceromotor response, abdominal sensitivity and real time place preference assays (Aim 2). Implementation of this new technology will provide unique access to understanding bladder functionality without the need for implantation of potentially damaging bladder catheters or electrodes. This technology could thus lead to novel insights into the mechanisms of bladder control and pain. Additionally, the refinement of this novel technology and viral delivery methods for optogenetic channels, could lead to development of future therapies for patients with bladder pain and dysfunction.

抽象的 美国有数百万人患有膀胱功能障碍和间质性疼痛 膀胱炎/膀胱疼痛综合征和膀胱过度活动症是许多这些疾病的潜在病理。 人们对此知之甚少，这是目前大多数治疗方法无效的主要原因。 本期，我们课题组设计并测试了一种植入式无线光电系统，用于监测和监测 调节膀胱功能。 膨胀时，设备几何形状的变化会线性增加电阻，然后可以直接关联 我们在应变计上安装了微型发光二极管 (μLED)， 可用于激活光敏视蛋白以进行神经元活动的光遗传学调节。 µLED 连接到植入式基站，可对膀胱进行无线控制和监测 这项新技术消除了植入可能损坏的膀胱导管或膀胱导管的需要。 电极，并为我计划使用的清醒、自由活动的大鼠提供了独特的膀胱功能。 视蛋白的病毒传递和一种测量膀胱周长动态变化的新型应变仪， 分别调节和监测膀胱功能 我的初步数据显示应变计的变化。 阻力与传统的膀胱活动测量（如膀胱内压）相关，并且病毒式传播 我计划递送抑制性视蛋白，古视紫红质（Arch），可以延迟麻醉大鼠的膀胱收缩。 测试膀胱传入神经中表达的病毒转导 Arch 降低频率和增加频率的能力 清醒动物中环磷酰胺 (CYP) 诱发膀胱炎后的排尿量（目标 1a 和 b）。 使用我们新开发的无线技术来实现闭环系统，该系统可以识别增加的 膀胱收缩频率并启动光遗传学抑制以使排尿正常化（目标 1c）。 我计划使用我们的无线 μLED 应变计来解决 IC/BPS 患者最常见的问题。 以确定膀胱传入神经中病毒转导的 Arch 的激活是否足以 减弱 CYP 诱导的膀胱炎大鼠的膀胱过敏反应。 内脏运动反应、腹部敏感性和实时位置偏好测定（目标 2）。 这项新技术将为了解膀胱功能提供独特的途径，而无需 因此，植入具有潜在破坏性的膀胱导管或电极可能会带来新的成果。 此外，还对这项新技术进行了改进。 和用于光遗传学通道的病毒传递方法，可能会导致未来患者疗法的开发 伴有膀胱疼痛和功能障碍。