Activating Peripheral Glia to Relieve Visceral Pain in Animal Models of Urological Chronic Pelvic Pain Syndrome (UCPPS)

PROJECT SUMMARY/ABSTRACT There are significant gaps in our knowledge of how peripheral GFAP+ glia regulate sensory neuronal activity and their involvement in primary afferent sensitization. The lack of understanding of the roles of peripheral glial cells, mainly due to our inability of selectively perturbing signaling pathways in subpopulations of peripheral glia

in vivo, presents an important obstacle in developing creative and effective strategies for investigating glial contribution in chronic diseases. The long-term goal of this project is to target GFAP+ satellite glial cells (SGCs) for gene therapies for preventing and treating peripheral sensitization. The objective of this proposal is to

identify signaling pathways underlying SGC-neuron interaction in the sensory ganglia, as well as to characterize the translatome changes in sensory SGC signaling involved in visceral pain and bladder dysfunction. Strong preliminary data and past findings in sensory SGCs in the context of chronic pain led to the

central hypothesis that Gq-GPCR signaling in SGCs potently decreases the excitability and activity in bladder- projecting sensory neurons and contributes to neural control of bladder functions. This hypothesis will be tested by pursuing three specific aims: 1) Test the hypothesis that sensory satellite glial Gq-GPCR signaling

decreases bladder afferent sensitivity and alters micturition in physiological conditions and in inflammation- induced visceral pain and bladder overactivity model; 2) Identify the molecular link between satellite glial Gq- GPCR activation and decreased sensory neuronal excitability; and 3) Discover the changes in sensory satellite

glial translatome during the onset and chronic phase of inflammation-induced pelvic pain and lower urinary tract symptoms (LUTS). Under the first aim, targeted and selective gene manipulation in peripheral GFAP+ glia will be utilized to study the role of SGCs in physiological and pathological regulation of bladder afferent

excitability. In the second aim, the cellular and molecular mechanism underlying SGC-neuron interaction will be identified in sensory ganglia explants using approaches similar to those used in studying CNS glial-neuronal interactions in situ. Additional experiments will be performed in vivo to test the therapeutic potential of targeting

the identified signaling pathway(s) for alleviating visceral pain and bladder overactivity in this aim. Under the third aim, TRAP technology will be employed to identify changes in sensory SGC translatome as a function of inflammation-induced bladder overactivity and pelvic painin a non-biased manner.The proposed research is

significant because 1) it demonstrates a new pharmacogenetic approach for selectively activating peripheral glia in vivo, which benefits broader research community in Neuro-urology research; 2) it is expected to fill the knowledge gap on glial modulation of bladder function, a completely unexplored research field with high

therapeutic potential; 3) it provides the first line of evidence for subsequent pre-clinical and clinical trials of targeting satellite glial cells and peripheral adenosine receptors in treating pelvic pain; and 4) it lays the groundwork for genetic analysis on specific subsets of peripheral glia during physiology and disease.