Bio

Bio

I am a postdoctoral research fellow in Dr. Gary Steinberg's lab in the Department of Neurosurgery. My main interest is to understand the underlying cellular and molecular mechanisms after stroke and to find the therapeutic targets for brain repair and stroke recovery. My PhD. thesis work demonstrated the acute and sustained neuroprotection by the pharmacological hypothermia in ischemic stroke animal model, providing a novel hypothermia treatment for stroke application. Before that, I detected the role of innate immune signaling pathways from toll-like-receptor family in myocardial infarction. My current work focuses on using optogenetic strategies to stimulate the targeted neurons for brain repair after stroke and detecting the neural circuit and molecular mechanisms underlying the stroke recovery.

Honors & Awards

  • Trainee Professional Development Award, Society for Neuroscience (2019)
  • Postdoctoral Fellowship, American Heart Association (AHA ) (2017-2019)
  • Best Poster award in Third Annual cardiovascular Research Institute Symposium, Baylor College of Medicine, Houston, TX (2015)
  • Dean?s Awards for Excellence, Baylor College of Medicine, Houston, TX (2015)
  • First Place Award for Best Posters at the 27th BCM Annual Graduate Student Symposium,, Baylor College of Medicine, Houston, TX (2015)
  • Third place poster award, Medical World Americas Conference, Houston, TX (2015)
  • Pre-doctoral Fellowship, American Heart Association (AHA ) (2013-2015)
  • Outstanding graduation thesis, Nanjing Medical University, Nanjing, Jiangsu, China (2010)

Boards, Advisory Committees, Professional Organizations

  • Member, American Heart Association (2011 - Present)
  • Member, American Physiological Society (2012 - Present)

Professional Education

  • Doctor of Philosophy, Baylor College Of Medicine (2016)
  • Master of Science, Nanjing Medical University (2009)
  • Doctor of Medicine, Yangzhou University Medical College (2004)

Stanford Advisors

Contact

Research & Scholarship

Current Research and Scholarly Interests

My current research focuses on:
1) using optogenetic strategies to stimulate targeted neurons for brain repair after stroke.
2) detecting the neural circuit and molecular mechanisms underlying stroke recovery.

Publications

All Publications

  • Unique Subtype of Microglia in Degenerative Thalamus After Cortical Stroke. Stroke Cao, Z. n., Harvey, S. S., Chiang, T. n., Foltz, A. G., Lee, A. G., Cheng, M. Y., Steinberg, G. K. 2021: STROKEAHA120032402

    Abstract

    Stroke disrupts neuronal functions in both local and remotely connected regions, leading to network-wide deficits that can hinder recovery. The thalamus is particularly affected, with progressive development of neurodegeneration accompanied by inflammatory responses. However, the complexity of the involved inflammatory responses is poorly understood. Herein we investigated the spatiotemporal changes in the secondary degenerative thalamus after cortical stroke, using targeted transcriptome approach in conjunction with histology and flow cytometry.Cortical ischemic stroke was generated by permanent occlusion of the left middle cerebral artery in male C57BL6J mice. Neurodegeneration, neuroinflammatory responses, and microglial activation were examined in naive and stroke mice at from poststroke days (PD) 1 to 84, in both ipsilesional somatosensory cortex and ipsilesional thalamus. NanoString neuropathology panel (780 genes) was used to examine transcriptome changes at PD7 and PD28. Fluorescence activated cell sorting was used to collect CD11c+ microglia from ipsilesional thalamus, and gene expressions were validated by quantitative real-time polymerase chain reaction.Neurodegeneration in the thalamus was detected at PD7 and progressively worsened by PD28. This was accompanied by rapid microglial activation detected as early as PD1, which preceded the neurodegenerative changes. Transcriptome analysis showed higher number of differentially expressed genes in ipsilesional thalamus at PD28. Notably, neuroinflammation was the top activated pathway, and microglia was the most enriched cell type. Itgax (CD11c) was the most significantly increased gene, and its expression was highly detected in microglia. Flow-sorted CD11c+ microglia from degenerative thalamus indicated molecular signatures similar to neurodegenerative disease-associated microglia; these included downregulated Tmem119 and CX3CR1 and upregulated ApoE, Axl, LpL, CSF1, and Cst7.Our findings demonstrate the dynamic changes of microglia after stroke and highlight the importance of investigating stroke network-wide deficits. Importantly, we report the existence of a unique subtype of microglia (CD11c+) with neurodegenerative disease-associated microglia features in the degenerative thalamus after stroke.

    View details for DOI 10.1161/STROKEAHA.120.032402

    View details for PubMedID 33412903

  • ime-Course Characterization of Blood-Brain Barrier Disruption in Secondary Thalamic Injury After Stroke Cao, Z., Harvey, S., Pendharkar, A., Chiang, T., Cheng, M., Steinberg, G. LIPPINCOTT WILLIAMS & WILKINS. 2020

    View details for Web of Science ID 000590040201358

  • Inflammatory Responses in the Secondary Thalamic Injury After Cortical Ischemic Stroke. Frontiers in neurology Cao, Z., Harvey, S. S., Bliss, T. M., Cheng, M. Y., Steinberg, G. K. 2020; 11: 236

    Abstract

    Stroke is one of the major causes of chronic disability worldwide and increasing efforts have focused on studying brain repair and recovery after stroke. Following stroke, the primary injury site can disrupt functional connections in nearby and remotely connected brain regions, resulting in the development of secondary injuries that may impede long-term functional recovery. In particular, secondary degenerative injury occurs in the connected ipsilesional thalamus following a cortical stroke. Although secondary thalamic injury was first described decades ago, the underlying mechanisms still remain unclear. We performed a systematic literature review using the NCBI PubMed database for studies that focused on the secondary thalamic degeneration after cortical ischemic stroke. In this review, we discussed emerging studies that characterized the pathological changes in the secondary degenerative thalamus after stroke; these included excitotoxicity, apoptosis, amyloid beta protein accumulation, blood-brain-barrier breakdown, and inflammatory responses. In particular, we highlighted key findings of the dynamic inflammatory responses in the secondary thalamic injury and discussed the involvement of several cell types in this process. We also discussed studies that investigated the effects of blocking secondary thalamic injury on inflammatory responses and stroke outcome. Targeting secondary injuries after stroke may alleviate network-wide deficits, and ultimately promote stroke recovery.

    View details for DOI 10.3389/fneur.2020.00236

    View details for PubMedID 32318016

  • Cellular and Molecular Characterization of Microglia in Secondary Thalamic Injury After Ischemic Stroke Cao Zhijuan, Harvey, S., Chiang, T., Foltz, A., Cheng, M., Steinberg, G. LIPPINCOTT WILLIAMS & WILKINS. 2019

    View details for Web of Science ID 000478733400334

  • RNA-Sequencing Analysis Revealed a Distinct Motor Cortex Transcriptome in Spontaneously Recovered Mice After Stroke STROKE Ito, M., Aswendt, M., Lee, A. G., Ishizaka, S., Cao, Z., Wang, E. H., Levy, S. L., Smerin, D. L., McNab, J. A., Zeineh, M., Leuze, C., Goubran, M., Cheng, M. Y., Steinberg, G. K. 2018; 49 (9): 2191?99

    View details for DOI 10.1161/STROKEAHA.118.021508

    View details for Web of Science ID 000442858100035

  • RNA-Sequencing Analysis Revealed a Distinct Motor Cortex Transcriptome in Spontaneously Recovered Mice After Stroke. Stroke Ito, M. n., Aswendt, M. n., Lee, A. G., Ishizaka, S. n., Cao, Z. n., Wang, E. H., Levy, S. L., Smerin, D. L., McNab, J. A., Zeineh, M. n., Leuze, C. n., Goubran, M. n., Cheng, M. Y., Steinberg, G. K. 2018; 49 (9): 2191?99

    Abstract

    Background and Purpose- Many restorative therapies have been used to study brain repair after stroke. These therapeutic-induced changes have revealed important insights on brain repair and recovery mechanisms; however, the intrinsic changes that occur in spontaneously recovery after stroke is less clear. The goal of this study is to elucidate the intrinsic changes in spontaneous recovery after stroke, by directly investigating the transcriptome of primary motor cortex in mice that naturally recovered after stroke. Methods- Male C57BL/6J mice were subjected to transient middle cerebral artery occlusion. Functional recovery was evaluated using the horizontal rotating beam test. A novel in-depth lesion mapping analysis was used to evaluate infarct size and locations. Ipsilesional and contralesional primary motor cortices (iM1 and cM1) were processed for RNA-sequencing transcriptome analysis. Results- Cluster analysis of the stroke mice behavior performance revealed 2 distinct recovery groups: a spontaneously recovered and a nonrecovered group. Both groups showed similar lesion profile, despite their differential recovery outcome. RNA-sequencing transcriptome analysis revealed distinct biological pathways in the spontaneously recovered stroke mice, in both iM1 and cM1. Correlation analysis revealed that 38 genes in the iM1 were significantly correlated with improved recovery, whereas 74 genes were correlated in the cM1. In particular, ingenuity pathway analysis highlighted the involvement of cAMP signaling in the cM1, with selective reduction of Adora2a (adenosine receptor A2A), Drd2 (dopamine receptor D2), and Pde10a (phosphodiesterase 10A) expression in recovered mice. Interestingly, the expressions of these genes in cM1 were negatively correlated with behavioral recovery. Conclusions- Our RNA-sequencing data revealed a panel of recovery-related genes in the motor cortex of spontaneously recovered stroke mice and highlighted the involvement of contralesional cortex in spontaneous recovery, particularly Adora2a, Drd2, and Pde10a-mediated cAMP signaling pathway. Developing drugs targeting these candidates after stroke may provide beneficial recovery outcome.

    View details for PubMedID 30354987

  • TRPV1-mediated Pharmacological Hypothermia Promotes Improved Functional Recovery Following Ischemic Stroke. Scientific reports Cao, Z. n., Balasubramanian, A. n., Pedersen, S. E., Romero, J. n., Pautler, R. G., Marrelli, S. P. 2017; 7 (1): 17685

    Abstract

    Hypothermia shows promise for stroke neuroprotection, but current cooling strategies cause undesirable side effects that limit their clinical applications. Increasing efforts have focused on pharmacological hypothermia as a treatment option for stroke. Previously, we showed that activation of a thermoregulatory ion channel, transient receptor potential vanilloid 1 (TRPV1), by dihydrocapsaicin (DHC) produces reliable hypothermia. In this study, we investigate the effects of TRPV1-mediated hypothermia by DHC on long-term ischemic stroke injury and functional outcome. Hypothermia initiated at 3.5?hours after stroke significantly reduced primary cortical injury. Interestingly, hypothermia by DHC also significantly reduced secondary thalamic injury, as DHC-treated stroke mice exhibited 53% smaller thalamic lesion size. DHC-treated stroke mice further demonstrated decreased neuronal loss and astrogliosis in the thalamus and less thalamic fiber loss by diffusion tensor imaging (DTI). Importantly, a single 8?hour treatment of hypothermia by DHC after stroke provided long-term improvement in functional outcome, as DHC-treated mice exhibited improved behavioral recovery at one month post-stroke. These findings indicate that TRPV1-mediated hypothermia is effective in reducing both primary cortical injury and remote secondary thalamic injury, and a single treatment can produce persistent effects on functional recovery. These data highlight the therapeutic potential for TRPV1 agonism for stroke treatment.

    View details for DOI 10.1038/s41598-017-17548-y

    View details for PubMedID 29247238

    View details for PubMedCentralID PMC5732157

  • Transient Receptor Potential Melastatin 8 Channel Inhibition Potentiates the Hypothermic Response to Transient Receptor Potential Vanilloid 1 Activation in the Conscious Mouse CRITICAL CARE MEDICINE Feketa, V. V., Zhang, Y., Cao, Z., Balasubramanian, A., Flores, C. M., Player, M. R., Marrelli, S. P. 2014; 42 (5): E355-E363

    Abstract

    Mild decrease in core temperature (therapeutic hypothermia) provides lasting neuroprotection following cardiac arrest or cerebral ischemia. However, current methods for producing therapeutic hypothermia trigger a cold-defense response that must be countered by sedatives, muscle paralytics, and mechanical ventilation. We aimed to determine methods for producing hypothermia in the conscious mouse by targeting two transient receptor potential channels involved in thermoregulation, two transient receptor potential (TRP) channels involved in thermoregulation, TRP vanilloid 1 (TRPV1) and TRP melastatin 8 (TRPM8).Controlled prospective animal study.Research laboratory at academic medical center.Conscious unrestrained young and aged male mice.Mice were treated with the TRPV1 agonist dihydrocapsaicin, a TRPM8 inhibitor ("compound 5"), or their combination and the effects on core temperature (Tcore) were measured by implanted thermocouples and wireless transponders.TRPV1 agonist dihydrocapsaicin produced a dose-dependent (2-4 mg/kg s.c.) drop in Tcore. A loading dose followed by continuous infusion of dihydrocapsaicin produced a rapid and prolonged (> 6 hr) drop of Tcore within the therapeutic range (32-34°C). The hypothermic effect of dihydrocapsaicin was augmented in aged mice and was not desensitized with repeated administration. TRPM8 inhibitor "compound 5" (20 mg/kg s.c.) augmented the drop in core temperature during cold exposure (8°C). When "compound 5" (30 mg/kg) was combined with dihydrocapsaicin (1.25-2.5 mg/kg), the drop in Tcore was amplified and prolonged.Activating warm receptors (TRPV1) produced rapid and lasting hypothermia in young and old mice. Furthermore, hypothermia induced by TRPV1 agonists was potentiated and prolonged by simultaneous inhibition of TRPM8.

    View details for DOI 10.1097/CCM.0000000000000229

    View details for Web of Science ID 000335383900004

    View details for PubMedID 24595220

  • Pharmacologically induced hypothermia via TRPV1 channel agonism provides neuroprotection following ischemic stroke when initiated 90 min after reperfusion AMERICAN JOURNAL OF PHYSIOLOGY-REGULATORY INTEGRATIVE AND COMPARATIVE PHYSIOLOGY Cao, Z., Balasubramanian, A., Marrelli, S. P. 2014; 306 (2): R149-R156

    Abstract

    Traditional methods of therapeutic hypothermia show promise for neuroprotection against cerebral ischemia-reperfusion (I/R), however, with limitations. We examined effectiveness and specificity of pharmacological hypothermia (PH) by transient receptor potential vanilloid 1 (TRPV1) channel agonism in the treatment of focal cerebral I/R. Core temperature (T(core)) was measured after subcutaneous infusion of TRPV1 agonist dihydrocapsaicin (DHC) in conscious C57BL/6 WT and TRPV1 knockout (KO) mice. Acute measurements of heart rate (HR), mean arterial pressure (MAP), and cerebral perfusion were measured before and after DHC treatment. Focal cerebral I/R (1 h ischemia + 24 h reperfusion) was induced by distal middle cerebral artery occlusion. Hypothermia (>8 h) was initiated 90 min after start of reperfusion by DHC infusion (osmotic pump). Neurofunction (behavioral testing) and infarct volume (TTC staining) were measured at 24 h. DHC (1.25 mg/kg) produced a stable drop in T(core) (33°C) in naive and I/R mouse models but not in TRPV1 KO mice. DHC (1.25 mg/kg) had no measurable effect on HR and cerebral perfusion but produced a slight transient drop in MAP (<6 mmHg). In stroke mice, DHC infusion produced hypothermia, decreased infarct volume by 87%, and improved neurofunctional score. The hypothermic and neuroprotective effects of DHC were absent in TRPV1 KO mice or mice maintained normothermic with heat support. PH via TRPV1 agonist appears to be a well-tolerated and effective method for promoting mild hypothermia in the conscious mouse. Furthermore, TRPV1 agonism produces effective hypothermia in I/R mice and significantly improves outcome when initiated 90 min after start of reperfusion.

    View details for DOI 10.1152/ajpregu.00329.2013

    View details for Web of Science ID 000329854000007

    View details for PubMedID 24305062

    View details for PubMedCentralID PMC3921315

  • CpG-ODN, the TLR9 agonist, attenuates myocardial ischemia/reperfusion injury: Involving activation of PI3K/Akt signaling BIOCHIMICA ET BIOPHYSICA ACTA-MOLECULAR BASIS OF DISEASE Cao, Z., Ren, D., Ha, T., Liu, L., Wang, X., Kalbfleisch, J., Gao, X., Kao, R., Williams, D., Li, C. 2013; 1832 (1): 96-104

    Abstract

    Toll-like receptors (TLRs) have been implicated in myocardial ischemia/reperfusion (I/R) injury. The TLR9 ligand, CpG-ODN has been reported to improve cell survival. We examined effect of CpG-ODN on myocardial I/R injury.Male C57BL/6 mice were treated with either CpG-ODN, control-ODN, or inhibitory CpG-ODN (iCpG-ODN) 1h prior to myocardial ischemia (60min) followed by reperfusion. Untreated mice served as I/R control (n=10/each group). Infarct size was determined by TTC straining. Cardiac function was examined by echocardiography before and after myocardial I/R up to 14days.CpG-ODN administration significantly decreased infarct size by 31.4% and improved cardiac function after myocardial I/R up to 14days. Neither control-ODN nor iCpG-ODN altered I/R-induced myocardial infarction and cardiac dysfunction. CpG-ODN attenuated I/R-induced myocardial apoptosis and prevented I/R-induced decrease in Bcl2 and increase in Bax levels in the myocardium. CpG-ODN increased Akt and GSK-3? phosphorylation in the myocardium. In vitro data suggested that CpG-ODN treatment induced TLR9 tyrosine phosphorylation and promoted an association between TLR9 and the p85 subunit of PI3K. Importantly, PI3K/Akt inhibition and Akt kinase deficiency abolished CpG-ODN-induced cardioprotection.CpG-ODN, the TLR9 ligand, induces protection against myocardial I/R injury. The mechanisms involve activation of the PI3K/Akt signaling pathway.

    View details for DOI 10.1016/j.bbadis.2012.08.008

    View details for Web of Science ID 000313932000011

    View details for PubMedID 22917564

    View details for PubMedCentralID PMC3518630

  • The TIR/BB-loop mimetic AS-1 protects the myocardium from ischaemia/reperfusion injury CARDIOVASCULAR RESEARCH Cao, Z., Hu, Y., Wu, W., Ha, T., Kelley, J., Deng, C., Chen, Q., Li, C., Li, J., Li, Y. 2009; 84 (3): 442-451

    Abstract

    Innate immune and inflammatory responses are involved in myocardial ischaemia/reperfusion (I/R) injury. The interleukin-1 receptor (IL-1R)-mediated, MyD88-dependent nuclear factor kappa B (NF-kappaB) activation pathway plays an important role in the induction of innate immunity and inflammation. However, the role of the IL-1R-MyD88 pathway in myocardial I/R injury has not been thoroughly investigated. We hypothesized that inhibition of the interaction of IL-1R with MyD88 will attenuate myocardial ischaemic injury through reducing inflammatory responses.Male C57BL/6 mice were subjected to myocardial ischaemia (45 min) followed by reperfusion (4 h). In the treatment group, after mice were subjected to ischaemia (45 min), the TIR/BB-loop mimetic (AS-1), which inhibits the interaction of IL-1R with MyD88, was administered immediately before reperfusion. Hearts were harvested and cellular proteins were isolated for immunoprecipitation and immunoblotting. AS-1 administration significantly decreased infarct size by 32.92% compared with the untreated I/R group. Ejection fraction and fractional shortening in AS-1-treated mice were also significantly increased by 18.0 and 25.6%, respectively, compared with the untreated I/R group. AS-1 administration significantly decreased the I/R-increased interaction between IL-1R and MyD88, attenuated the I/R-increased NF-kappaB binding activity, and reduced levels of inflammatory cytokines and adhesion molecules in the myocardium compared with the untreated I/R group. In addition, AS-1 administration significantly decreased myocardial myeloperoxidase activity by 23.6% and neutrophil infiltration in the myocardium compared with the untreated I/R group.The results demonstrated an important role for the IL-1R-mediated MyD88-dependent signalling pathway in myocardial I/R injury. The data suggest that modulation of the IL-1R/MyD88 interaction could be a strategy for reducing myocardial ischaemic injury.

    View details for DOI 10.1093/cvr/cvp234

    View details for Web of Science ID 000272084800016

    View details for PubMedID 19586942

  • Carbamylated erythropoietin protects the myocardium from acute ischemia/reperfusion injury through a PI3K/Akt-dependent mechanism SURGERY Xu, X., Cao, Z., Cao, B., Li, J., Guo, L., Que, L., Ha, T., Chen, Q., Li, C., Li, Y. 2009; 146 (3): 506-514

    Abstract

    Erythropoietin (EPO) and carbamylated erythropoietin (CEPO) can protect tissue from injury; however, CEPO has its protective effect in the absence of erythropoietic stimulation. The mechanism whereby CEPO protects heart from acute ischemia/reperfusion (I/R) injury remains unknown.BALB/c mice were subjected to myocardial ischemia for 45 min followed by reperfusion for 4 h, and they received a single dose of CEPO intraperitoneal at the onset of reperfusion. Myocardial infarct size and cardiac function were assessed. The association of erythropoietin receptor with beta common receptor (betacR) was examined. The level of Akt phosphorylation in the myocardium was assayed as well as a series of downstream target genes of PI3K/Akt,including p-GATA-4, GATA-4, MHC, and troponin I.CEPO administration immediately before reperfusion decreased infarction by 40% and increased ejection fraction (27%) and fractional shortening (22%), compared with untreated ischemic hearts (P < .05 each). CEPO promoted association of the EPO receptor and betacR. Furthermore, CEPO administration increased the levels of phospho-Akt in the myocardium by 59% (P < .05). A PI3K inhibitor, wortmannin, blocked the beneficial effect of CEPO on infarct size and cardiac function and attenuated the CEPO-induced Akt phosphorylation. CEPO also increased the expression of p-GATA-4, GATA-4, myosin heavy chain, and troponin I.A single dose of CEPO at the onset of reperfusion attenuated acute myocardial I/R injury in the mouse. CEPO-induced cardioprotection appears to be mediated through a PI3K/Akt-dependent mechanism.

    View details for DOI 10.1016/j.surg.2009.03.022

    View details for Web of Science ID 000269680600017

    View details for PubMedID 19715808

  • Dephosphorylation of cardiomyocyte Cx43 is associated with myocardial ischemia and reperfusion injury Journal of Nanjing Medical University Cao, Z., Xu, X., Que, L., Chen, Q., Li, Y. 2009; 23 (3): 163-167
  • Nonhematopoietic erythropoietin derivative protects cardiomyocytes from hypoxia/reoxygenation-induced apoptosis Journal of Nanjing Medical University Xu, X., Shan, X., Cao, Z., Wu, M., Chen, Q., Li, Y. 2008; 22 (2): 71-74

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