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).
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. The goal is to 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 controling micturition and the visceromotor reflex (a surrogate for bladder pain).
| Shimizu, Nobutaka; Doyal, Mark F; Goins, William F et al. (2018) Corrigendum to 'Morphological Changes in Different Populations of Bladder Afferent Neurons Detected by Herpes Simplex Virus (HSV) Vectors with Cell-type-specific Promoters in Mice with Spinal Cord Injury' [Neuroscience 364 (2017) 190-201]. Neuroscience 381:161 |
| DeBerry, Jennifer J; Samineni, Vijay K; Copits, Bryan A et al. (2018) Differential Regulation of Bladder Pain and Voiding Function by Sensory Afferent Populations Revealed by Selective Optogenetic Activation. Front Integr Neurosci 12:5 |
| Shimizu, Nobutaka; Doyal, Mark F; Goins, William F et al. (2017) Morphological changes in different populations of bladder afferent neurons detected by herpes simplex virus (HSV) vectors with cell-type-specific promoters in mice with spinal cord injury. Neuroscience 364:190-201 |
