19839-Gao, Xiang

Xiang Gao, PhD

Assistant Research Professor of Neurological Surgery

NB 503E
Indianapolis, IN
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Xiang Gao, PhD, joined Indiana University School of Medicine faculty in 2016. He is an assistant research professor in the Department of Neurological Surgery specializing in traumatic brain injury (TBI). Dr. Gao studies the pathological changes and underlying mechanisms of brain trauma with the goal of developing new intervention for treatment.

Dr. Gao was pursuing his PhD at the Shanghai Institute of Biochemistry and Cell Biology, China where his neurological studies prepared him with skills for scientific research. His postdoctoral training at University of Kentucky and IU School of Medicine eventually led him to an interest in brain trauma.   

Dr. Gao currently serves as a principal investigator in a laboratory located in Stark Neurosciences Research Institute, where his main interests are to find an effective way to mitigate, or even prevent, cell death and dendritic/synaptic degeneration post TBI; to explore the potential therapeutic interventions for repairing damaged neural circuitries; and to study the molecular mechanisms underlie immune response and neuroinflammation post-trauma.

Dr. Gao's journey reflects a remarkable commitment to understanding and addressing the traumatic brain injury, as he strives to forge innovative solutions that could potentially benefit the lives of TBI patients.

In his free time, Dr. Gao enjoys being with his wife and their children for variety of activities, such as different ball games, hiking, fishing and traveling.

Key Publications

  1. Gao X, Arlotta P, Macklis JD, Chen J. Conditional knock-out of beta-catenin in postnatal-born dentate gyrus granule neurons results in dendritic malformation. J Neurosci. 2007 27(52)
  2. Gao X, Smith GM, Chen J. Impaired dendritic development and synaptic formation of postnatal-born dentate gyrus granular neurons in the absence of brain-derived neurotrophic factor signaling. Exp Neurol. 215 (2009) 178–190
  3. Gao X, Deng P, Xu ZC, Chen J. Moderate Traumatic Brain Injury Causes Acute Dendritic and Synaptic Degeneration in the Hippocampal Dentate Gyrus. PLoS One. 2011 Sept; 6(9)
  4. Gao X, Wang X, Xiong W, Chen J. In vivo reprogramming reactive glia into iPSCs to produce new neurons in the cortex following traumatic brain injury. Sci Rep. 2016 Mar 9; 6:22490
  5. Gao X*, Li W, Syed F, Yuan F, Li P, Yu Q *. PD-L1 signaling in reactive astrocytes counteracts neuroinflammation and ameliorates neuronal damage after traumatic brain injury. Journal of Neuroinflammation. 2022 Feb. 08, 19(43). *: corresponding author

Titles & Appointments

  • Assistant Research Professor of Neurological Surgery
  • Education
    2000 PhD Shanghai Institute of Biochemistry and Cell Biology
    1992 BS Nanjing University
  • Research
    1. Preventing progressive spine loss to improve function recover after repetitive mild traumatic brain injury (rmTBI). Youth, high school and college students, and professional athletes who participated in contact sports with a history of repetitive mTBI (rmTBI) show increased rates of cognitive impairment, psychiatric disorders, and even Chronic Traumatic Encephalopathy (CTE) in some cases. To date, there is not Food and Drug Administration (FDA) approved effective treatment for rmTBI, mostly due to our poorly understanding of the pathophysiology following rm Excitatory synapses loss has been suggested to play a major role in the etiology of rmTBI. Our lab first demonstrated that single mTBI causes extensive dendritic spine loss without inducing obvious cell death and axonal damage, and it positively correlated with functional impairment. Recent study in rmTBI model in our lab also revealed the dramatic spine loss after injury. The mechanisms of spine loss after mTBI are also very poorly understood. We found that spine loss was not transient after rmTBI. Instead, it was a progressive process lasting from days to at least a week, which hardly to be attributed to excitotoxicity solely, an acute and transient event after initial injury. Recent studies in other CNS diseases, such as Alzheimer’s disease (AD), Parkinson’s disease (PD), and Huntington’s disease (HD) revealed the important role of inflammation in spine loss. It has been shown that microglia (macrophages) could engulf spine through a process mediated by activation of a complement system, which highlighted a possible way of spine elimination in other pathological conditions, including rmTBI. Therefore, we propose that engulfment by reactive microglia via activation of the complement system is one of the major mechanisms underlying the progressive spine loss after rmTBI. Thus, complements inhibition may prevent spine loss and result in better functional outcomes. This study will augment our knowledge of the etiology of rmTBI, and will highlight the complements as new targets for developing therapeutic interventions to treat the neurological disorders caused by rmTBI.
    2. The function of proliferative reactive astrocyte after TBI. Astrocytes react to brain injury with progressive changes in gene expression, morphological hypertrophy, and proliferation referred as astrogliosis. The beneficial or detrimental effects of proliferative reactive astrocytes are constantly under debate, and the underlying molecular mechanisms are poorly understood. Our long-term goal is to dissect the mechanisms underlying the proliferation of reactive astrocytes and its biological function in the hippocampus after TBI, and in order to find the vital targets for TBI treatment. We are studying the role of platelet-derived growth factor receptor alpha (PDGFRa) signaling in regulating reactive astrocyte proliferation and we believe that proliferative reactive astrocytes are neuroprotective by favoring synapse preservation and regeneration following TBI. Completion of mechanism study will provide an ideal tool to explore the function of proliferative reactive astrocyte in the hippocampus and which in turn to identify vital targets for therapeutic intervention aiming at functional improvement after TBI. This project is innovative because we reveal for the first time the role of PDGFRa in regulating reactive astrocyte proliferation post-trauma using state-of-art inducible conditional knockout/knockin technique and discover the neuroprotective aspects of proliferative reactive astrocytes in injured hippocampus.
    3. The molecular mechanisms underlying immune responses and inflammation after TBI. Overwhelming evidence has revealed that TBI triggers sterile neuroimmune and neuroinflammatory responses that can have both detrimental and beneficial effects. While appropriate acute and transient neuroimmune responses facilitate the repair and adaptation of injured brain tissues, prolonged and excessive neuroinflammatory responses may accelerate TBI brain damage. The mechanisms that control the intensity and duration of neuroimmune and neuroinflammatory responses in TBI largely remain elusive. We used TBI to study the role of immune checkpoints (ICPs) in the regulation of neuroimmune and neuroinflammatory responses in the brain in vivo. We found that de novo expression of PD-L1 (programmed death-ligand 1), a key inhibitory ICP that exerts dual inhibitory signals to suppress the activity of PD-1-expressing T cells via the PD-1/PD-L1 axis and a novel intrinsic reverse signaling, was robustly and specifically induced in reactive astrocytes. These PD-L1-positive astrocytes, including newly generated proliferative astrocytes were highly enriched to form a dense zone around the TBI lesion. Inhibition of PD-L1 signaling suppressed the cell survive and prompted the expression of neuroinflammatory related genes, such as STAT3 and its downstream target CCL2, which resulted in increase of inflammatory Ly-6CHigh monocytes/macrophages (M/M?) infiltration, brain tissue cavity size, and subsequent motor and emotional dysfunction in TBI mice. We therefore hypothesize that neuroprotective PD-L1 signaling is involved in astrocytic scar formation andPD-L1-positive astrocytes act as a brake to control TBI-induced neuroimmune and neuroinflammatory responses via counteracting CCL2 expression through suppressing STAT3 signaling. Our research will demonstrate that PD-L1-positive astrocytes exert their dual inhibitory signals to affect the immune responses and functional outcome following TBI, thereby opening a novel avenue to study the role of ICPs in TBI pathophysiology. Our research provides insights into development of ICP and its related signal pathway regulators to improve TBI functional outcomes.
    4. The molecular mechanisms underlying great neuroprotection of Dexmedetomidine, a FDA approved sedative drug after trauma. Systematic application of therapeutic hypothermia (TH) in the acute phase post-TBI has been shown to be neuroprotective in both experimental and human studies. Despite the discourage data from multicenter randomized clinic trails (RCT), which might be due to unsuccessfully achieve desired temperature (330C) within therapeutic time window and other limitations, it is important to continually the topic of TH and its utility in neuroprotection. Our long-term goal is to find a target to improve the therapeutic effects of hypothermia by either developing strategy for on-site using or extending the therapeutic window, and investigating the putative synergistic effect of combining hypothermia with other neuroprotectants. Our pilot study showed that in a mouse model of moderate TBI, the one i.p. dose of the FDA-approved sedative Dexmedetomidine (Dex, 100mg/kg) rapidly generated long last TH (32-350C) in an ambient temperature at 24.50 This modulation of body temperature without application of any auxiliary heating and cooling equipment suggests that Dex can be potentially used on-site. Importantly, Dex treated TBI mice with induced TH exerted greater functional improvement than conventional TH or Dex treated TBI mice with normothermia, reflecting by further reduced lesion area in cortex and better behavior test score. Dex has also been proven to activate multiple signaling pathways which can be neuroprotective. Therefore, we believe that Dexmedetomidine exerts a great neuroprotective effect on TBI via a synergistic mechanism of inducing early hypothermia and activating inherent neuroprotective signaling. This research is innovative because we reveal for the first time the potential role of “old” FDA approved Dexmedetomidine in treating TBI patients, which could be rapidly assimilated into the clinical practice.
    5. The new intervention to alleviate the symptoms after TBI via managing function associated neural circuit. TBI causes a wide range of pathological changes in the brain that lead to multiple neurological disorders. These disorders remain incurable mostly due to the lack of knowledge about the connections that wire pathological changes to the specific symptom after TBI. Recent studies and emerging new technologies have facilitated function/behavior associated neural circuitry identification. This provides an opportunity to bridge the gap between pathologies and functional outcomes after trauma. Moreover, it opens a new avenue to treat neurological disorder via directly targeting associated neural circuitry by neuronal activity management post-trauma. Risk-taking behavior is a commonly reported emotional disorder among young TBI patients and veterans with PTSD. The deficits of risk-taking behavior post-TBI have drastically negative impact on patient’s social and professional outcomes, their safety, their own and their relative’s quality of life. To date, no treatment for this devastating disorder. We replicated this symptom in a controlled cortical impact (CCI) mouse model of moderate TBI and studied the alteration of its associated neural circuit following trauma. Our preliminary data demonstrated the dramatic increase of risky behavior in the TBI mice, even 12 weeks post-injury. Staining with antibody against c-fos, a marker for neuronal activity revealed that TBI significantly damaged hippocampal-hypothalamic circuit with a remarkable decrease of neuronal activity in ventral hippocampal CA1 (vCA1) region and lateral hypothalamic area (LHA). The neuronal activity in these two regions, which belong to basolateral amygdala (BLA)-ventral hippocampus CA1 (vCA1)-hypothalamus area (LHA) circuit, a direct route by which the hippocampus can rapidly influence innate anxiety behavior, has been suggested to be critical for controlling risky activity as well. Taking advantage of chemogenetic system Designer Receptors Exclusively Activated by Designer Drugs (DREADD), we manually increased vCA1 neuronal activity of TBI mice via overexpressing Dreadd receptor (hM3D(Gq)-mcherry, activator) in this region by adeno-associated viruses (AAV) mediated delivering. The Dreadd infected vCA1 neurons not only projected into LHA, but also enhanced the neuronal activity in LHA when they were activated by clozapine N-oxide (CNO), a specific ligand for Dreadd receptor activation. Further, the increase of neuronal activity in vCA1 and LHA may eventually lead to the mitigation of risky behavior after TBI. Taken together, the disruption of hippocampal-hypothalamic circuit is the molecular mechanism underlies risk-taking behavior after TBI and risky behavior is able to be mitigated or even prevented by neural circuit management using DREADD chemogenetic system. Successful completion of the proposed study will provide new insights to support the long term goal to better understand the mechanisms that underlie specific neurological dysfunction after TBI, a critical step to identify targets for focused interventions. Although, virus mediated chemogenetics successfully modulates the neuronal activity in vCA1 and may mitigate risk-taking behavior in mice, this procedure is too invasive for clinical use. Thus, the future studies with exploring novel noninvasive neuromodulation methods, such as using magnetic strategies for neuronal activity management are next steps aiming at achieving the same effects practically.

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