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overview As a glia biologist, I am interested in the neuromodulatory role of peripheral glial fibrillary acidic protein-expressing (GFAP+) glia in micturition and their therapeutic potential in benign bladder disorder. The Xie lab works in close collaboration with other research labs in the Basic and Translational Urology Research Program in the Division of Urology, Department of Surgery. Research project 1. The analgesic role of sensory satellite glial cells in bladder overactivity and chronic pelvic pain Patients with urological chronic pelvic pain syndrome (UCPPS) experience chronic pelvic pain (CPP) and lower urinary tract symptoms (LUTS). The UCPPS symptoms are closely associated with nociceptive sensitization in the nervous system, which underlies visceral allodynia and hyperalgesia. Previous studies suggested that afferent hypersensitivity in bladder-projecting sensory neurons plays an important role in the generation and the maintenance of UCPPS symptoms, especially bladder pain and urinary frequency. We have identified that satellite glial activation in lumbosacral sensory ganglia alleviates inflammatory pain in mice. In addition, terminal Schwann cell signaling also contribute to nerve injury-induced neuropathic pain. These data suggested the strong therapeutic potential of peripheral GFAP+ glial signaling in acute control of afferent excitability. Our fundings suggest that Gq-GPCR activation in peripheral GFAP+ glia might be a promising and highly innovative approach to alleviate the symptoms of bladder overactivity and pain. The current work focuses on 1) developing experimental approaches for targeted activation of Gq-GPCR signaling pathways in sensory SGCs; 2) assessing the changes in lumbosacral bladder afferent sensitivity following glial Gq-GPCR activation; and 3) evaluating the glial activation-induced changes in LUTS and visceral hypersensitivity in vivo and in mouse models of UCPPS. Gq-coupled Designer Receptors Exclusively Activated by Designer Drugs (Gq-DREADD) is used to selectively activate Gq-GPCR signaling cascades in lumbosacral sensory SGCs via targeted adeno-associated virus (AAV) delivery. Afferent sensitivity and bladder functions are evaluated in vivo by well-established and clinically relevant visceral nociceptive assays and urodynamic assays. This project aims to characterize the role of SGC Gq-GPCR signaling in regulating visceral nociception in vivo as well as test its therapeutic potential to reverse pain and voiding dysfunction in UCPPS patients. Relevant publications: Xie AX, Pan XQ, Meacham RB, Malykhina AP. (2018) The Expression of Transcription Factors MeCP2 and CREB Is Modulated in Inflammatory Pelvic Pain. Front Syst Neurosci. 2019 Jan 11;12:69. doi: 10.3389/fnsys.2018.00069. eCollection 2018. Xie AX*, Madayag A, Minton SK, McCarthy KD, Malykhina AP. (2020) Sensory satellite glial Gq-GPCR activation alleviates inflammatory pain via peripheral adenosine 1 receptor activation. *Corresponding author. Sci Rep. 2020 Aug 25;10(1):14181. doi: 10.1038/s41598-020-71073-z. Xie AX†*, Taves S†, McCarthy KD. (2021) Nuclear factor Kappa B-COX2 pathway activation in non-myelinating Schwann cells is necessary for the maintenance of neuropathic pain in mice. *Corresponding author. Front. Cell. Neurosci. 14 January 2022 doi: 10.3389/fncel.2021.782275 Xie AX, Iguchi N, Clarkson TC, Malykhina AP. (2022) Pharmacogenetic inhibition of sensory afferent excitability alleviates bladder VEGF signaling-induced visceral hypersensitivity in an animal model of UCPPS. PLOS ONE, in press. Xie AX†, Iguchi N†, Malykhina AP*. Long-term follow-up of TREK-1 KO mice reveals the development of bladder hypertrophy and impaired bladder smooth muscle contractility with age. in Review Yesupatham SK, Malykhina AP, Xie AX*. Transcriptome Analysis in Lumbosacral Dorsal Root Ganglia Suggests Sex-specific Mechanisms Underlying Visceral Hypersensitivity. In Review Research project 2. The neuroactive role of autonomic satellite glial cells in modulating bladder physiology The long-term goal of conducting glia research is to target glial signaling for disease treatments. But first, we need to understand the role of glia in vivo and in intact neural circuits. We have shown that pharmacogenetic activation of Gq-GPCR signaling in sympathetic SGCs in superior cervical ganglia significantly increases heart rate, cardio output, and blood pressure. Moreover, persist activation of sympathetic SGCs results in hypotension in sex-dependent manner. Our finding was the first report on the role of SGCs in autonomic ganglia. Current research in the Xie lab aims to reveal the molecular mechanisms underlying the neuroactive effect of satellite glia-neuron interactions in the sympathetic ganglia. In addition, we are actively testing the hypothesis that Gq-GPCR activation in SGCs in the major pelvic ganglia, the autonomic ganglia innervating the urinary bladder will potentiate autonomic-driven bladder contractions and changes in micturition. Relevant publications: Agulhon C, Boyt KM, Xie AX, Friocourt F, Roth BL, McCarthy KD. (2013) Modulation of the autonomic nervous system and behaviour by acute glial cell Gq protein-coupled receptor activation in vivo. J Physiol. 2013 Nov 15;591(22):5599-609. doi: 10.1113/jphysiol.2013.261289. Xie AX, Petravicz, J, McCarthy KD. (2015) Molecular approaches for manipulating astrocytic signaling in vivo. Front Cell Neurosci. 2015 Apr 21;9:144. doi: 10.3389/fncel.2015.00144 Xie AX*, Lee JJ, McCarthy KD. (2016) Ganglionic GFAP+ Glial Gq-GPCR Signaling Enhances Heart Functions in vivo. *Corresponding author. JCI Insight. 2017;2(2):e90565. doi:10.1172/jci.insight.90565. Xie AX*, Chaia A, McCarthy KD. (2017) Targeting sympathetic glia for treating cardiovascular diseases. *Corresponding author. Receptors and Clinical Investigation. 2017;4:e1572. doi: 10.14800/rci.1572.

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