Novel viral tools for control of bladder function and pain

用于控制膀胱功能和疼痛的新型病毒工具

• 批准号: 9060550
• 负责人: BRIAN M DAVIS
• 金额: $ 28.14万
• 依托单位: UNIVERSITY OF PITTSBURGH AT PITTSBURGH
• 依托单位国家: 美国
• 财政年份: 2015
• 资助国家: 美国
• 起止时间: 2015-09-30 至 2017-07-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9060550
• 关键词: Address; Adenosine; Affect; Afferent Neurons; Animal Model; Autonomic nervous system; Basic Science; Behavioral; Biological; Biology; Bladder; Bladder Control; Chemicals; Chloride Channels; Chronic; Clinic; Consensus; Cyclophosphamide; Cystitis; Data; Disease; Effectiveness; Esthesia; Experimental Models; Fiber; Funding; Genes; Genetic; Glutamates; Goals; HSV vector; Halorhodopsins; Homeostasis; Human; Increased frequency of micturition; Inflammation; Injury; Interstitial Cystitis; Ivermectin; Laboratories; Light; Malignant Neoplasms; Measurement; Micturition Reflex; Modeling; Mus; Nervous system structure; Neurogenic Inflammation; Nociceptive Reflex; Organ; Pain; Pancreatitis; Parents; Patients; Pelvis; Peptides; Peripheral; Pharmaceutical Preparations; Phase; Phenotype; Physiological; Play; Population; Quality of life; Reflex action; Regulation; Research; Role; Safety; Sensory; Signal Transduction; Spinal cord injury patients; Substance P; Symptoms; Technology; Testing; Transgenic Mice; Urination; Urologic Diseases; Viral; Virus; Visceral; base; bladder pain; design; effective therapy; genetic technology; meetings; mouse model; neuroregulation; novel; pain inhibition; programs; promoter; public health relevance; research study; response; retrograde transport; small molecule; tool; transmission process; vector

 DESCRIPTION (provided by applicant): There are a number of diseases that affect the bladder that do not have adequate treatments. For example, interstitial cystitis (IC) and overactive active bladder (OAB) are chronic urological disorders characterized by increased micturition frequency and urgency; IC is distinct from OAB in that patients additionally suffer from pelvic/suprapubic pain. Likewise, inability to empty the bladder is a common debilitating problem (often associated with severe pain) among spinal cord injury patients and for some, is the major contributor to decreased quality of life. In all of these examples, it is not completely clear how distinct subpopulations of bladder afferents differentially drive these symptoms and thus, there are basic science issues that need to be addressed before mechanism-based approaches can be explored. Our laboratory (the Davis lab) has been using genetic mouse lines that express channelrhodopsin (ChR2) or halorhodopsin (NpHR) in sensory neurons. Preliminary data presented in this application demonstrate that these light sensitive channels can be used to regulate the visceromotor reflex (a surrogate for bladder pain) as well as control the micturition reflex. Unfortunately, our previous studies rely on transgenic mouse models that have significant limitations inherent in a genetic technology that produces permanent gene changes that are activated during embyogenesis and lack temporal and spatial control. New tools are needed to determine if our observations can be extended to other relevant animal models, as well as developed into effective treatments for human. This application is in response to RFA-RM-15-002 that strives to develop tools that will "be tailored to the specific use case/mechanism under study" and whose "end deliverable is a tool or technology, NOT a biological discovery" (from Common Fund pdf provided to potential applicants). The co-PI on this application (Dr. Glorioso) is a pioneer in the use of sensory neuron-specific viruses that can be used to activate or silence sensory neurons. In particular, he has developed a novel, druggable chloride channel (ivermectin) construct that is effective in blocking somatic pain. In addition, the Glorioso lab has produced other novel viral constructs that have passed phase I human trials, allowing the proposed studies to meet the criteria of translatability that is require by this RFA. This "proof of concept" data while exciting, will only be applicable to human bladder (as well as other animal models) if appropriate strategies are developed that will allow expression of these molecules in humans. The proposed research program will combine the efforts of these two laboratories; one studying pain and regulation of visceral organ function and a second that has a long track-record in designing sensory neuron-specific viruses that can be used to target expression of novel genes to primary afferents. We will produce and test 9 different viral constructs (expressing three novel genes, under three different promoters), targeted to different sensory neuron populations and determine their effectiveness for control micturition and the visceromotor reflex (a surrogate for bladder pain).

 描述（由申请人提供）：有许多影响膀胱的疾病没有足够的治疗方法。 例如，间质性膀胱炎（IC）和膀胱过度活动症（OAB）是以排尿频率和尿急增加为特征的慢性泌尿系统疾病; IC与OAB的不同之处在于患者还患有盆腔/耻骨上疼痛。 同样，无法排空膀胱是脊髓损伤患者中常见的衰弱问题（通常与严重疼痛相关），并且对于某些人来说，是生活质量下降的主要原因。 在所有这些例子中， 明确膀胱传入神经的不同亚群如何不同地驱动这些症状，因此，在探索基于机制的方法之前，需要解决一些基础科学问题。 我们的实验室（戴维斯实验室）一直在使用在感觉神经元中表达通道视紫红质（ChR 2）或盐视紫红质（NpHR）的遗传小鼠品系。 本申请中提供的初步数据表明，这些光敏通道可用于调节内脏反射（膀胱疼痛的替代物）以及控制排尿反射。 不幸的是，我们以前的研究依赖于转基因小鼠模型，这些模型具有遗传技术固有的显著局限性，该遗传技术产生在胚胎发生期间激活的永久性基因变化，并且缺乏时间和空间控制。 需要新的工具来确定我们的观察是否可以扩展到其他相关的动物模型，以及开发成对人类有效的治疗方法。 本申请是对RFA-RM-15-002的回应，RFA-RM-15-002致力于开发“针对研究中的特定用例/机制”的工具，并且其“最终可交付成果是一种工具或技术，而不是生物学发现”（来自提供给潜在申请人的共同基金pdf）。 该应用程序的共同PI（Glorioso博士）是使用感觉神经元特异性病毒的先驱， 用于激活或沉默感觉神经元。 特别是，他开发了一种新的，可药用的氯离子通道（伊维菌素）结构，有效地阻断躯体疼痛。 此外，Glorioso实验室还生产了其他新的病毒结构，这些结构已经通过了I期人体试验，使拟议的研究能够满足RFA所要求的可翻译性标准。 这种“概念证明”数据虽然令人兴奋，但只有在开发出允许这些分子在人体中表达的适当策略时，才适用于人类膀胱（以及其他动物模型）。 拟议中的研究计划将联合收割机结合这两个实验室的努力;一个研究疼痛和内脏器官功能的调节，另一个在设计感觉神经元特异性病毒方面有着悠久的历史，这些病毒可用于将新基因的表达靶向初级传入神经。 我们将生产和测试9种不同的病毒构建体（表达三种新基因，在三种不同的启动子下），靶向不同的感觉神经元群体，并确定它们对控制排尿和内脏反射（膀胱疼痛的替代品）的有效性。