Research in the Gu laboratory focuses on understanding the molecular mechanisms of redox modulation, particularly molecular mechanisms of perturbations in cell-cell and cell-matrix signaling due to nitrosative and oxidative stress, resulting in neurovascular impairment in neurodegenerative diseases. Another research focus is to investigate the mechanism of matrix metalloproteinases (MMPs) in the pathogenesis of ischemic and traumatic brain injuries. The Gu laboratory uses multi-disciplinary approaches and paradigms to conduct translational research. Our toolbox includes cell-free protein interaction, primary neuron cultures including biofidelic 3D cultures, and in vivo rodent models of neurodegenerative diseases, as well as neurobehavioral assessment, digital pathology and quantitative proteomic analyses.
Nitrosative/oxidative stress alters functions of both extracellular and intracellular key molecules, contributing to neuronal cell death and injury, mitochondrial fragmentation, protein misfolding, transcriptional regulation, and redox homeostasis. We have demonstrated that botanicals and their active components are able to mitigate nitrosative/oxidative stress and inflammatory responses in neurons and glial cells, as well as protect the brain against cerebral ischemic injury. We discovered a novel signaling cascade activating MMP-9 through S-nitrosylation, resulting in excessive extracellular proteolysis which leads to neuronal apoptosis. A highly specific inhibitor SB-3CT blocks MMP-9 activity, rescues neurons from apoptosis, and ameliorates neurovascular impairment from both ischemic and traumatic injuries. We demonstrated that activatable cell-penetrating peptides reveal in vivo MMP-9 activity as a surrogate indicator of MMP-mediated neurovascular impairment.
My lab applied systems biology by developing a number of cutting-edge techniques for quantitative proteomics, such as nitroDIGE as well as with isobaric reagents including iodoTMT and DiART, to globally profile differential levels of proteins and to detect specific cysteine-based protein translational modifications (PTM). These quantitative proteomics techniques allow us to investigate redox-based protein modulation in the nervous system. Ultimately, the endeavor of our studies supported with these techniques and resources may lead to identifying potential biomarkers and therapeutic targets for neurodegenerative diseases.
We are also passionate about the training of scientists, physicians, and graduate students from all over the world, which as of now includes Mexico, Puerto Rico, China, Indian, Japan, Philippines, Turkey, Israel, Libya, Cote D’lvoire, Ghana, Nigeria, Cameroon, and South Africa.
- Neurovascular impairment and dysfunction after acute brain injuries and in chronic neurodegenerative diseases
- Nitrosative and oxidative stress in cell signaling
- Perturbations in cell-cell and cell-matrix signaling
- Discovery of novel biomarkers and therapeutic targets
Areas of Expertise
- In vivo rodent models manifesting features of neurological diseases, such as ischemic stroke, traumatic brain and spinal cord injuries
- Primary cell cultures including biofidelic 3D cultures
- Cognitive, motor-sensory, memory and learning behavioral assessment
- Neuropathology, digital pathology and ultrastructural analysis
- Quantitative proteomics and bioinformatics
Education & Training
Tianjin Medical University, Tianjin, China
Burnham Institute for Medical Research, La Jolla, CA
Cell Biology and Neuroscience, University of Texas Medical Branch (UTMB) at Galveston, TX
Awards & Honors
- American Heart Association (AHA) including Beginning Grant-in Aid and National Science Development Award
- The Dana Foundation Brain Immuno-Imaging Program
- The NFL Charities Foundation
- The Department of Defense (DOD)
- The National Institutes of Health (NIH)
- The State of Missouri Spinal Cord Injury Research Program
- The State of Indiana Brain and Spinal Cord Injury Research Program
- Gu Z, Karl M, Yan B, Kridel S, Cui JK, Strongin A, Smith JW, Liddington CR and Lipton SA. S-nitrosylation of matrix metalloproteinases: Signaling pathway to neuronal cell death. Science2002, 297:1186-90.
- Yao D., Gu Z., Nakamura T., Shi Z-S., Ma Y., Masliah E. and Lipton S.A. Nitrosative stress linked to sporadic Parkinson’s disease: S-nitrosylation of parkin regulates its E3 ligase activity. Natl. Acad. Sci. USA 2004, 101:10810-14.
- Gu Z, Cui JK, Brown S, Fridman R., Mobashery S, Strongin A and Lipton SA. A highly specific inhibitor of matrix metalloproteinase-9 rescues laminin from proteolysis and neurons from apoptosis in transient focal cerebral ischemia. Neurosci. 2005, 25:6401-8.
- Uehara T, Nakamura T, Yao D, Shi Z-S, Gu Z, Ma Y, Masliah E, Nomura Y, and Lipton S.A. S-Nitrosylated protein-disulfide isomerase links protein misfolding to neurodegeneration. Nature 2006, 441:315-7.
- Takahashi H, Shin Y, Cho S-J, Zago WM, Nakamura T, Gu Z, Ma Y, Furukawa H, Liddington R, Zhang D, Tong G, Chen HSV, and Lipton SA. Hypoxia enhances S-nitrosylation-mediated NMDA receptor inhibition via a thiol oxygen sensor motif. Neuron 2007, 53:53-64.
- Fang JG, Nakamura T, Cho DH, Gu Z, Lipton SA. S-Nitrosylation of peroxiredexin 2 promotes oxidative stress-induced neuronal cell death in Parkinson’s disease. Natl. Acad. Sci. USA2007, 104:18742-7.
- Cho D-H., Nakamura T., Fang J., Cieplak P., Godzik A., Gu Z., and Lipton S.A. S-Nitrosylation of Drp1 mediates β-Amyloid-related mitochondrial fission and neuronal injury. Science 2009, 324:102-5.
- Cui J, Chen S, Zhang C, Meng F, Wu W, Hu R, Hadass O, Lehmidi T, Blair GJ, Lee M, Chang M, Mobashery S, Sun GY, Gu Z. Inhibition of MMP-9 by a selective gelatinase inhibitor protects neurovasculature from embolic focal cerebral ischemia. Mol Neurodegener. 2012 May 15;7:21.
- Hadass O, Tomlinson BN, Gooyit M, Chen S, Purdy JJ, Walker JM, Zhang C, Giritharan AB, Purnell W, Robinson CR 2nd, Shin D, Schroeder VA, Suckow MA, Simonyi A, Sun GY, Mobashery S, Cui J, Chang M, Gu Z. Selective inhibition of matrix metalloproteinase-9 attenuates secondary damage resulting from severe traumatic brain injury. PLoS ONE 2013 Oct 23;8(10):e76904.
- Chen Z, Shin D, Chen S, Mikhail K, Hadass O, Tomlinson BN, Korkin D, Shyu C-R, Cui J, Anthony DC, Gu Z. Histological quantitation of brain injury using whole slide imaging: A pilot validation study in mice. PLoS ONE 2014 Mar 17; 9(3):e92133.
- Qu Z, Meng F, Bomgarden R, Viner R, Li J, Rogers J, Cheng J, Greenlief C, Cui J, Lubahn D, Sun G, Gu Z. Proteomic Quantification and Site-Mapping of S-Nitrosylated Proteins Using Isobaric iodoTMT Reagents. Proteome Res. 2014, 13, 3200−3211.
- Zhou H, Qu Z, Mossine VV, Nknolise DL, Li J, Chen Z, Cheng J, Greenlief CM, Mawhinney TP, Brown PN5, Fritsche KL, Hannink M, Lubahn DB, Sun GY, Gu Z. Proteomic Analysis of the Effects of Aged Garlic Extract and Its FruArg Component on Lipopolysaccharide-Induced Neuroinflammatory Response in Microglial Cells. PLoS ONE 2014 Nov 24;9(11):e113531.
- Lee M, Chen Z, Tomlinson BN, Gooyit M, Hesek D, Juárez MR, Nizam R, Boggess B, Lastochkin E, Schroeder VA, Wolter WR, Suckow MA, Cui J, Mobashery S, Gu Z, Chang M. Water-Soluble MMP-9 Inhibitor Reduces Lesion Volume after Severe Traumatic Brain Injury. ACS Chem Neurosci. 2015 Oct 21;6(10):1658-64.
- Chen S, Meng F, Chen Z, Tomlinson BN, Wesley JM, Sun GY, Whaley-Connell AT, Sowers JR, Cui J, Gu Z. Two-dimensional Zymography Differentiates Gelatinase Isoforms in Stimulated Microglial Cells and in Brain Tissues of Acute Brain Injuries. PLoS ONE 2015 Apr 10;10(4):e0123852.
- Qu Z, Greenlief CM, Gu Z. Quantitative Proteomic Approaches for Analysis of Protein S-Nitrosylation. J Proteome Res. 2016 Jan 4;15(1):1-14.
- Chen S, Cui J, Jiang T, Olson ES, Cai QY, Yang M, Wu W, Guthrie JM, Robertson JD, Lipton SA, Ma L, Tsien RY, Gu Z. Gelatinase Activity Imaged by Activatable Cell-Penetrating Peptides in Cell-Based and in Vivo Models of Stroke. J Cereb Blood Flow Metab. 2017 Jan;37(1):188-200.