An optogenetic-based control paradigm for neuromodulation of bladder function following spinal cord injury

脊髓损伤后膀胱功能神经调节的基于光遗传学的控制范例

基本信息

批准号：
10540806
负责人：
Aaron David Mickle
金额：
$ 19.06万
依托单位：
UNIVERSITY OF FLORIDA
依托单位国家：
美国
项目类别：
财政年份：
2021
资助国家：
美国
起止时间：
2021-04-01 至 2024-06-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10540806
关键词：
Address American Anatomy Animal Model Animals Area Ataxia Biotechnology Bladder Bladder Control Bladder Diseases Bladder Dysfunction Catheterization Cells Central Nervous System Clinical Research Complex Contracts Development Devices Efferent Neurons Event Fiber Frequencies Functional disorder Gene Delivery Genes Goals Human Injury Light Lower urinary tract Medicine Methods Micturition Reflex Modeling Motor Motor Neurons Muscle Nerve Fibers Nervous System control Neurons Opsin Optics Patients Pattern Peripheral Peripheral Nervous System Persons Physiological Population Process Proteins Rattus Relaxation Sensory Smooth Muscle Specificity Sphincter Spinal cord injury Spinal cord injury patients Stimulus Striated Muscles System Techniques Technology Testing Urethra Urethral sphincter Urine Viral Viral Vector Virus Visual Work cell type cholinergic constriction delivery vehicle detrusor muscle gene delivery system improved innovation lower urinary tract symptoms nerve supply neural neuroregulation next generation novel optogenetics preclinical study prevent promoter renal damage sensory input social symptomatic improvement targeted treatment urinary

项目摘要

PROJECT SUMMARY More than 17,000 Americans suffer from spinal cord injuries every year, and many of these patients suffer from lower urinary tract dysfunction. One of these bladder disorders is detrusor-sphincter dyssynergia, where the detrusor muscle, which constricts to push urine out of the bladder, and the urethral sphincters, which relax to allow urine to pass out the urethra, cannot coordinate their actions to produce a void. Electrical neuromodulation technologies can be effective in improving symptoms of lower urinary tract dysfunction but due the complexity of the circuit and neural systems involved these therapies are unable to initiate a coordinated voiding contraction on-demand. To address these limitations, we plan to develop an optogenetic neuromodulatory approach to target and independently control the two main neuronal systems (parasympathetic and somatic motor) that are integral to the voiding reflex. Optogenetic neuromodulation involves genetically expressing optically activated proteins in neurons to modulate their activity with light stimulus. Using this method, we plan to express excitatory opsins in parasympathetic neurons innervating the detrusor by using promoter restricted expression and anatomically limited viral delivery (Aim 1). Activation of these neurons leads to detrusor/bladder contractions. To inhibit tonic urethral sphincter tone, we will use a similar approach to target the somatic motor neurons innervating the external urethral sphincter with inhibitory opsins (Aim 2). Inhibition of these neurons leads to sphincter relaxation. We will test the specificity of expression, potential off target effects, as well as the physiological effects of opsin activation in naïve and in a rat model of spinal cord injury. Finally, we will develop a control paradigm to coordinate activation of detrusor with urethral sphincter relaxation, to initiate coordinated and complete emptying of the bladder (Aim 3). The proposed project will develop innovative neuromodulatory techniques to control bladder function. Further development of refined and efficient neuromodulation techniques is the first step in developing closed-loop therapies to treat bladder dysfunction associated with spinal cord injury. Additionally, these techniques will have wide applicability in other fields of peripheral nervous system gene delivery and cell- type specific neuromodulation. Advances in neuromodulation of bladder function will bring us closer to goal of improving the lives of patients with spinal cord injury.

项目概要每年有超过 17,000 名美国人遭受脊髓损伤，其中许多患者患有下尿路功能障碍之一是逼尿肌-括约肌协同失调。逼尿肌收缩，将尿液推出膀胱；尿道括约肌放松，将尿液排出膀胱。允许尿液从尿道排出，但无法协调其动作以产生空隙。技术可以有效改善下尿路功能障碍的症状，但由于技术的复杂性这些疗法涉及的回路和神经系统无法启动协调的排尿收缩为了解决这些限制，我们计划开发一种光遗传学神经调节方法来靶向。并独立控制两个不可或缺的主要神经系统（副交感神经和躯体运动神经系统）光遗传学神经调节涉及基因表达光激活蛋白。使用这种方法，我们计划在神经元中表达兴奋性视蛋白。副交感神经元通过使用启动子限制表达和解剖学来支配逼尿肌有限的病毒传递（目标 1）。这些神经元的激活导致逼尿肌/膀胱收缩。尿道括约肌张力，我们将使用类似的方法来瞄准支配尿道括约肌张力的体运动神经元尿道外括约肌具有抑制性视蛋白（目标 2）。抑制这些神经元会导致括约肌松弛。我们将测试表达的特异性、潜在的脱靶效应以及视蛋白的生理效应最后，我们将开发一种控制范例来控制脊髓损伤。协调激活逼尿肌和尿道括约肌松弛，以启动协调和完全排空拟议项目将开发创新的神经调节技术来控制。膀胱功能的第一步是进一步开发精细且高效的神经调节技术。开发闭环疗法来治疗与脊髓损伤相关的膀胱功能障碍。这些技术将在其他周围神经系统基因传递领域和细胞- 膀胱功能神经调节的进步将使我们更接近目标改善脊髓损伤患者的生活。

项目成果

期刊论文数量（3）

专著数量（0）

科研奖励数量（0）

会议论文数量（0）

专利数量（0）

Evaluating the transduction efficiency of systemically delivered AAV vectors in the rat nervous system.

评估大鼠神经系统中系统递送的 AAV 载体的转导效率。

DOI：
发表时间：
2023
期刊：
影响因子：
0
作者：
Yang, Olivia J;Robilotto, Gabriella L;Alom, Firoj;Alemán, Karla;Devulapally, Karthik;Morris, Abigail;Mickle, Aaron D
通讯作者：
Mickle, Aaron D

Acute ampakines increase voiding function and coordination in a rat model of SCI.

急性安帕金可增强 SCI 大鼠模型的排尿功能和协调性。