Browsing by Author "Wang, Ying"

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    AAV-KLF7 Promotes Descending Propriospinal Neuron Axonal Plasticity after Spinal Cord Injury
    (hindawi publishing corporation, 2017) Li, Wen-Yuan; Wang, Ying; Zhai, Feng-Guo; Sun, Ping; Cheng, Yong-Xia; Deng, Ling-Xiao; Wang, Zhen-Yu; Neurological Surgery, School of Medicine
    DPSN axons mediate and maintain a variety of normal spinal functions. Unsurprisingly, DPSN tracts have been shown to mediate functional recovery following SCI. KLF7 could contribute to CST axon plasticity after spinal cord injury. In the present study, we assessed whether KLF7 could effectively promote DPSN axon regeneration and synapse formation following SCI. An AAV-KLF7 construct was used to overexpress KLF7. In vitro, KLF7 and target proteins were successfully elevated and axonal outgrowth was enhanced. In vivo, young adult C57BL/6 mice received a T10 contusion followed by an AAV-KLF7 injection at the T7–9 levels above the lesion. Five weeks later, overexpression of KLF7 was expressed in DPSN. KLF7 and KLF7 target genes (NGF, TrkA, GAP43, and P0) were detectably increased in the injured spinal cord. Myelin sparring at the lesion site, DPSN axonal regeneration and synapse formation, muscle weight, motor endplate morphology, and functional parameters were all additionally improved by KLF7 treatment. Our findings suggest that KLF7 promotes DPSN axonal plasticity and the formation of synapses with motor neurons at the caudal spinal cord, leading to improved functional recovery and further supporting the potential of AAV-KLF7 as a therapeutic agent for spinal cord injury.
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    Alteration of grey matter volume is associated with pain and quality of life in children with sickle cell disease
    (Elsevier, 2022-02) Wang, Ying; Hardy, Steven J.; Ichesco, Eric; Zhang, Pengyu; Harris, Richard E.; Darbari, Deepika S.; Anesthesia, School of Medicine
    Pain is the most common symptom experienced by patients with sickle cell disease (SCD) and is associated with poor quality of life. We investigated the association between grey matter volume (GMV) and the frequency of pain crises in the preceding 12 months and SCD-specific quality of life (QOL) assessed by the PedsQLTM SCD module in 38 pediatric patients with SCD. Using voxel-based morphometry methodology, high-resolution T1 structural scans were preprocessed using SPM and further analyzed in SPSS. The whole brain multiple regression analysis identified that perigenual anterior cingulate cortex (ACC) GMV was negatively associated with the frequency of pain crises (r = -0.656, P = 0.003). A two-group t-test analysis showed that the subgroup having pain crisis/crises in the past year also showed significantly lower GMV at left supratemporal gyrus than the group without any pain crisis (p=0.024). The further 21 pain-related regions of interest (ROI) analyses identified a negative correlation between pregenual ACC (r = -0.551, P = 0.001), subgenual ACC (r = -0.540, P = 0.001) and the frequency of pain crises. Additionally, the subgroup with poorer QOL displayed significantly reduced GMV in the parahippocampus (left: P = 0.047; right: P = 0.024). The correlations between the cerebral structural alterations and the accentuated pain experience and QOL suggests a possible role of central mechanisms in SCD pain.
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    Brain network hypersensitivity underlies pain crises in sickle cell disease
    (Springer Nature, 2024-03-27) Joo, Pangyu; Kim, Minkyung; Kish, Brianna; Nair, Vidhya Vijayakrishnan; Tong, Yunjie; Liu, Ziyue; O’Brien, Andrew R. W.; Harte, Steven E.; Harris, Richard E.; Lee, UnCheol; Wang, Ying; Biostatistics and Health Data Science, Richard M. Fairbanks School of Public Health
    Sickle cell disease (SCD) is a genetic disorder causing painful and unpredictable Vaso-occlusive crises (VOCs) through blood vessel blockages. In this study, we propose explosive synchronization (ES) as a novel approach to comprehend the hypersensitivity and occurrence of VOCs in the SCD brain network. We hypothesized that the accumulated disruptions in the brain network induced by SCD might lead to strengthened ES and hypersensitivity. We explored ES's relationship with patient reported outcome measures (PROMs) as well as VOCs by analyzing EEG data from 25 SCD patients and 18 matched controls. SCD patients exhibited lower alpha frequency than controls. SCD patients showed correlation between frequency disassortativity (FDA), an ES condition, and three important PROMs. Furthermore, stronger FDA was observed in SCD patients with a higher frequency of VOCs and EEG recording near VOC. We also conducted computational modeling on SCD brain network to study FDA's role in network sensitivity. Our model demonstrated that a stronger FDA could be linked to increased sensitivity and frequency of VOCs. This study establishes connections between SCD pain and the universal network mechanism, ES, offering a strong theoretical foundation. This understanding will aid predicting VOCs and refining pain management for SCD patients.
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    Chondroitinase ABC combined with Schwann cell transplantation enhances restoration of neural connection and functional recovery following acute and chronic spinal cord injury
    (Wolters Kluwer, 2025) Qu, Wenrui; Wu, Xiangbing; Wu, Wei; Wang, Ying; Sun, Yan; Deng, Lingxiao; Walker, Melissa; Chen, Chen; Dai, Heqiao; Han, Qi; Ding, Ying; Xia, Yongzhi; Smith, George; Li, Rui; Liu, Nai-Kui; Xu, Xiao-Ming; Neurological Surgery, School of Medicine
    Schwann cell transplantation is considered one of the most promising cell-based therapy to repair injured spinal cord due to its unique growth-promoting and myelin-forming properties. A the Food and Drug Administration-approved Phase I clinical trial has been conducted to evaluate the safety of transplanted human autologous Schwann cells to treat patients with spinal cord injury. A major challenge for Schwann cell transplantation is that grafted Schwann cells are confined within the lesion cavity, and they do not migrate into the host environment due to the inhibitory barrier formed by injury-induced glial scar, thus limiting axonal reentry into the host spinal cord. Here we introduce a combinatorial strategy by suppressing the inhibitory extracellular environment with injection of lentivirus-mediated transfection of chondroitinase ABC gene at the rostral and caudal borders of the lesion site and simultaneously leveraging the repair capacity of transplanted Schwann cells in adult rats following a mid-thoracic contusive spinal cord injury. We report that when the glial scar was degraded by chondroitinase ABC at the rostral and caudal lesion borders, Schwann cells migrated for considerable distances in both rostral and caudal directions. Such Schwann cell migration led to enhanced axonal regrowth, including the serotonergic and dopaminergic axons originating from supraspinal regions, and promoted recovery of locomotor and urinary bladder functions. Importantly, the Schwann cell survival and axonal regrowth persisted up to 6 months after the injury, even when treatment was delayed for 3 months to mimic chronic spinal cord injury. These findings collectively show promising evidence for a combinatorial strategy with chondroitinase ABC and Schwann cells in promoting remodeling and recovery of function following spinal cord injury.
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    Chx10+V2a interneurons in spinal motor regulation and spinal cord injury
    (Wolters Kluwer, 2023) Li, Wen-Yuan; Deng, Ling-Xiao; Zhai, Feng-Guo; Wang, Xiao-Yu; Li, Zhi-Gang; Wang, Ying; Neurological Surgery, School of Medicine
    Chx10-expressing V2a (Chx10+V2a) spinal interneurons play a large role in the excitatory drive of motoneurons. Chemogenetic ablation studies have demonstrated the essential nature of Chx10+V2a interneurons in the regulation of locomotor initiation, maintenance, alternation, speed, and rhythmicity. The role of Chx10+V2a interneurons in locomotion and autonomic nervous system regulation is thought to be robust, but their precise role in spinal motor regulation and spinal cord injury have not been fully explored. The present paper reviews the origin, characteristics, and functional roles of Chx10+V2a interneurons with an emphasis on their involvement in the pathogenesis of spinal cord injury. The diverse functional properties of these cells have only been substantiated by and are due in large part to their integration in a variety of diverse spinal circuits. Chx10+V2a interneurons play an integral role in conferring locomotion, which integrates various corticospinal, mechanosensory, and interneuron pathways. Moreover, accumulating evidence suggests that Chx10+V2a interneurons also play an important role in rhythmic patterning maintenance, left-right alternation of central pattern generation, and locomotor pattern generation in higher order mammals, likely conferring complex locomotion. Consequently, the latest research has focused on postinjury transplantation and noninvasive stimulation of Chx10+V2a interneurons as a therapeutic strategy, particularly in spinal cord injury. Finally, we review the latest preclinical study advances in laboratory derivation and stimulation/transplantation of these cells as a strategy for the treatment of spinal cord injury. The evidence supports that the Chx10+V2a interneurons act as a new therapeutic target for spinal cord injury. Future optimization strategies should focus on the viability, maturity, and functional integration of Chx10+V2a interneurons transplanted in spinal cord injury foci.
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    DBS in the restoration of motor functional recovery following spinal cord injury
    (Frontiers Media, 2024-12-04) Li, Wen-yuan; Qu, Wen-rui; Li, Yi; Wang, Shu-ying; Liu, Dong-ming; Deng, Ling-xiao; Wang, Ying; Neurological Surgery, School of Medicine
    The landscape of therapeutic deep brain stimulation (DBS) for locomotor function recovery is rapidly evolving. This review provides an overview of electrical neuromodulation effects on spinal cord injury (SCI), focusing on DBS for motor functional recovery in human and animal models. We highlight research providing insight into underlying cellular and molecular mechanisms. A literature review via Web of Science and PubMed databases from 1990 to May 29, 2024, reveals a growing body of evidence for therapeutic DBS in SCI recovery. Advances in techniques like optogenetics and whole-brain tractogram have helped elucidate DBS mechanisms. Neuronal targets sites for SCI functional recovery include the mesencephalic locomotor region (MLR), cuneiform nucleus (CNF), and nucleus raphe magnus (NRG), with pedunculopontine nucleus (PPN), periaqueductal gray (PAG), and nucleus ventroposterolateral thalami (VPL) for post-injury functional recovery treatment. Radiologically guided DBS optimization and combination therapy with classical rehabilitation have become an effective therapeutic method, though ongoing interventional trials are needed to enhance understanding and validate DBS efficacy in SCI. On the pre-clinical front, standardization of pre-clinical approaches are essential to enhance the quality of evidence on DBS safety and efficacy. Mapping brain targets and optimizing DBS protocols, aided by combined DBS and medical imaging, are critical endeavors. Overall, DBS holds promise for neurological and functional recovery after SCI, akin to other electrical stimulation approaches.
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    Descending motor circuitry required for NT-3 mediated locomotor recovery after spinal cord injury in mice
    (Nature Research, 2019-12-20) Han, Qi; Ordaz, Josue D.; Liu, Nai-Kui; Richardson, Zoe; Wu, Wei; Xia, Yongzhi; Qu, Wenrui; Wang, Ying; Dai, Heqiao; Zhang, Yi Ping; Shields, Christopher B.; Smith, George M.; Xu, Xiao-Ming; Neurological Surgery, School of Medicine
    Locomotor function, mediated by lumbar neural circuitry, is modulated by descending spinal pathways. Spinal cord injury (SCI) interrupts descending projections and denervates lumbar motor neurons (MNs). We previously reported that retrogradely transported neurotrophin-3 (NT-3) to lumbar MNs attenuated SCI-induced lumbar MN dendritic atrophy and enabled functional recovery after a rostral thoracic contusion. Here we functionally dissected the role of descending neural pathways in response to NT-3-mediated recovery after a T9 contusive SCI in mice. We find that residual projections to lumbar MNs are required to produce leg movements after SCI. Next, we show that the spared descending propriospinal pathway, rather than other pathways (including the corticospinal, rubrospinal, serotonergic, and dopaminergic pathways), accounts for NT-3-enhanced recovery. Lastly, we show that NT-3 induced propriospino-MN circuit reorganization after the T9 contusion via promotion of dendritic regrowth rather than prevention of dendritic atrophy.
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    Differential clinical characteristics across traditional Chinese medicine (TCM) Syndromes in patients with sickle cell disease
    (Frontiers Media, 2024-01-05) Wang, Ying; Wang, David D.; Pucka, Andrew Q.; O’Brien, Andrew R. W.; Harte, Steven E.; Harris, Richard E.; Anesthesia, School of Medicine
    Background: Pain is a common, debilitating, and poorly understood complication of sickle cell disease (SCD). The need for clinical pain management of SCD is largely unmet and relies on opioids as the main therapeutic option, which leads to a decreased quality of life (QoL). According to the literature, acupuncture has shown certain therapeutic effects for pain management in SCD. However, these clinical studies lack the guidance of Traditional Chinese Medicine (TCM) Syndrome Differentiation principles for treatment. Aim: To characterize differences in clinical presentation amongst TCM diagnosed Syndromes in SCD patients. Method: Fifty-two patients with SCD and 28 age- and sex-matched healthy controls (HCs) were enrolled in an ongoing trial of acupuncture. Each participant completed a series of questionnaires on pain, physical function, fatigue, sleep, anxiety, depression and QoL and underwent cold- and pressure-based quantitative sensory testing at baseline. Data on prescription opioid use over the 12 months prior to study enrollment was used to calculate mean daily morphine milligram equivalents (MME). Differences among the three TCM Syndromes were analyzed by one-way ANOVA followed by Tukey post hoc testing. Two-sample t-tests were used to compare SCD and HC groups. Results: TCM diagnosis criteria classified SCD patients into one of three TCM Syndromes: (a) Equal; (b) Deficiency; and (c) Stagnation. The Stagnation group exhibited higher pain interference, physical dysfunction, nociplastic pain, fatigue, anxiety, depression, MME consumption and lower sleep quality and QoL compared to the Equal group. Few differences were observed between HCs and the Equal SCD group across outcomes. Deficiency and Stagnation groups were differentiated with observed- and patient-reported clinical manifestations. Conclusion: These findings suggest that TCM diagnosed Syndromes in SCD can be differentially characterized using validated objective and patient-reported outcomes. Because characteristics of pain and co-morbidities in each SCD patient are unique, targeting specific TCM "Syndromes" may facilitate treatment effectiveness with a Syndrome-based personalized treatment plan that conforms to TCM principles. These findings lay the foundation for the development of tailored acupuncture interventions based on TCM Syndromes for managing pain in SCD. Larger samples are required to further refine and validate TCM diagnostic criteria for SCD.
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    Disrupting nNOS–PSD95 Interaction Improves Neurological and Cognitive Recoveries after Traumatic Brain Injury
    (Oxford University Press, 2020-06) Qu, Wenrui; Liu, Nai-Kui; Wu, Xiangbing; Wang, Ying; Xia, Yongzhi; Sun, Yan; Lai, Yvonne; Li, Rui; Shekhar, Anantha; Xu, Xiao-Ming; Psychiatry, School of Medicine
    Excessive activation of N-methyl-D-aspartate receptors (NMDARs) and the resulting neuronal nitric oxide synthase (nNOS) activation plays a crucial role in the pathogenesis of traumatic brain injury (TBI). However, directly inhibiting NMDARs or nNOS produces adverse side effects because they play key physiological roles in the normal brain. Since interaction of nNOS–PSD95 is a key step in NMDAR-mediated excitotoxicity, we investigated whether disrupting nNOS–PSD95 interaction with ZL006, an inhibitor of nNOS–PSD95 interaction, attenuates NMDAR-mediated excitotoxicity. In cortical neuronal cultures, ZL006 treatment significantly reduced glutamate-induced neuronal death. In a mouse model of controlled cortical impact (CCI), administration of ZL006 (10 mg/kg, i.p.) at 30 min postinjury significantly inhibited nNOS–PSD95 interaction, reduced TUNEL- and phospho-p38-positive neurons in the motor cortex. ZL006 treatment also significantly reduced CCI-induced cortical expression of apoptotic markers active caspase-3, PARP-1, ratio of Bcl-2/Bax, and phosphorylated p38 MAPK (p-p38). Functionally, ZL006 treatment significantly improved neuroscores and sensorimotor performance, reduced somatosensory and motor deficits, reversed CCI-induced memory deficits, and attenuated cognitive impairment. Histologically, ZL006 treatment significantly reduced the brain lesion volume. These findings collectively suggest that blocking nNOS–PSD95 interaction represents an attractive strategy for ameliorating consequences of TBI and that its action is mediated via inhibiting neuronal apoptosis and p38 MAPK signaling.
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    Divergent actions of Myofibroblast and Myocyte β2-Adrenoceptor in Heart Failure and Fibrotic Remodeling
    (American Heart Association, 2023) Deng, Bingqing; Zhang, Yu; Zhu, Chaoqun; Wang, Ying; Weatherford, Eric; Xu, Bing; Liu, Xuanhui; Conway, Simon J.; Abel, E. Dale; Xiang, Yang K.; Pediatrics, School of Medicine