Qian Shi, Ph.D.

Research

a member of Dr. Manzoor Bhat’s laboratory faculty, I have been focused on investigating the pathophysiological mechanisms underlying metabolic disorders, such as diabetes and cancer. There is strong evidence suggesting that the incidence of several types of cancer is increased in patients with diabetes, including leukemia, kidney cancer, colon cancer, and etc. We are particularly interested in the signaling pathways that link cancer and diabetes, among which are the mTOR signaling pathways and reactive oxygen species (ROS).  The mammalian target of Rapamycin (mTOR) is a central player in governing the cellular growth and metabolic homeostasis in response to many growth factors, cellular energy status, and amino-acid levels. The mutations on either TSC1 or TSC2 genes (that regulate mTOR) leads to a rare, multi-system genetic disorder, named tuberous sclerosis complex (TSC), that cause benign tumors to grow in the brain and on other vital organs such kidneys, heart, eyes, lungs, and skin. Because of the ineffectiveness of Rapamycin (inhibitor for mTORC1) in treating TSC, it’s worthy to investigate the alternative therapeutic options as the signaling pathways are not fully understood.

1. The role of mTOR signaling in myelinating glia

TSC severely affects neuronal function, both in CNS and PNS, leading to cognitive impairment, epilepsy, autism, and white matter abnormalities. However, its role in the process of myelination and associated CNS/PNS disorders remains to be fully understood. TSC mutated mice showed reduced myelination, disrupted paranodal domains in myelinated axons, and disorganized unmyelinated Remak bundles. We are particularly interested in elucidating the signaling pathways that linked mTOR to keys molecules in oligodendrocytes development, such as RNA–binding protein Quaking (Qk) and the 155 kDa glial Neurofascin (Nfasc^NF155). This will help design the new generation of inhibitors for treating TSC.

2. The role of mTOR/Nox4 in diabetic nephropathy

The current project aims to investigate the basic molecular mechanism that leads to the understanding of roles of renal proximal tubular epithelial cells in diabetes and in particular diabetic nephropathy (DN), one of the major complications of type 1 diabetes, and provide the novel therapeutic options. We found that high glucose up-regulates Nox4 expression in kidney, enhances NADPH oxidase activity and up-regulates fibronectin. Moreover, high glucose activates the mTOR pathway through enhancing mTORC1/2 activity. However, the precise mechanism by which mTORC2 regulates Nox4 expression/activation is still unknown. We are currently utilizing in vitro and in vivo approaches to establish the importance of possible mTORC2/Nox4 signaling pathway in mediating tubular epithelial cell injury in the diabetic environment, hoping to provide new therapeutic options for treating DN.

Awards & Accomplishments

Awards and Honors Mar. 2016         Advanced Postdoctoral Fellowship Award ($270,000 for 2016-2019), Juvenile Diabetes Research Foundation (JDRF) May 2016         Best Poster Awards for Postdoc/Student Research forum Department of Physiology, UTHSCSA Nov 2015         Travel Award to Advances in Research of ASN Annual Meeting American Society of Nephrology Mar. 2013         Postdoctoral Fellowship Award ($148,296 for 2013-2016), Juvenile Diabetes Research Foundation (JDRF) May 2013         Trainee Winner Award for Research Day Department of Medicine, UTHSCSA Dec. 2010         Pre-doctoral Travel Award American Society for Cell Biology 50th Annual Meeting Presentations Invited talk at JDRF Training Grantees Meeting, New York, Nov. 2017 Title: Novel therapeutic treatment of diabetic nephropathy. Invited talk at Huazhong University of Science and Technology, China. Dec. 2015 Title: The role of NOX4 in pathogenesis development of tuberous sclerosis complex and diabetic nephropathy. Poster Presentation at 2015 American Society for Cell Biology Annual Meeting Title: NADPH Oxidase 4 as a novel therapeutic target to treat Tuberous Sclerosis Complex. Oral presentation in 2013 Cold Spring Harbor Asia Conferences (Cell Signaling in Metabolism, Inflammation & Cancer), Suzhou, China Title: NADPH oxidase 4 Expression is up-Regulated in Tuberin Deficiency through mTOR: Implication for the Treatment of Tuberous Sclerosis Complex Poster Presentation at 2010 American Society for Cell Biology50th Annual Meeting Title: Cx50 Regulates Lens Differentiation via the Interaction with S Phase Kinase Protein 2 Oral presentation at 2009 International Gap Junction Conference Title: Opening of Connexin 43 Hemichannels is regulated through the Interaction with Integrin a5/b1 in Response to Mechanical Stimulation. Poster Presentation at 2009 International Gap Junction Conference Title: An Amino Acid Residue at the C-terminus of Connexin 50 Plays a Crucial Rolein Lens Epithelial-Fiber Cell Differentiation.

Publications

Google Scholar: https://scholar.google.com/citations?user=ALlPZhQAAAAJ&hl=en

Shi, Q., Chang, C., Saliba, A., and Bhat, M.A. (2022). Microglial mTOR Activation Upregulates Trem2 and Enhances β-Amyloid Plaque Clearance in the 5XFAD Alzheimer’s Disease Model. Journal of Neuroscience.
Zhang, W., Zhang, Q., Yang, N., Shi, Q., Su, H., Lin, T., He, Z., Wang, W., Guo, H., and Shen, P. (2022). Crosstalk between IL‐15Rα+ tumor‐associated macrophages and breast cancer cells reduces CD8+ T cell recruitment. Cancer Communications.
Shu, Y., Yang, N., Cheng, N., Zou, Z., Zhang, W., Bei, Y., Shi, Q., Qin, M., Zhu, W.-G., and Shen, P. (2022). Intervening pyruvate carboxylase stunts tumor growth by strengthening anti-tumor actions of tumor-associated macrophages. Signal transduction and targeted therapy 7, 1-3.
Shi, Q., Lee, D.-Y., Féliers, D., Abboud, H.E., Bhat, M.A., and Gorin, Y. (2020). Interplay between RNA-binding protein HuR and Nox4 as a novel therapeutic target in diabetic kidney disease. Molecular metabolism 36, 100968.
Kunisawa, K., Hatanaka, N., Shimizu, T., Kobayashi, K., Osanai, Y., Mouri, A., Shi, Q., Bhat, M.A., Nambu, A., and Ikenaka, K. (2020). Focal loss of the paranodal domain protein Neurofascin155 in the internal capsule impairs cortically induced muscle activity in vivo. Molecular brain 13, 1-10.
Shi, Q., Lin, Y.Q., Saliba, A., Xie, J., Neely, G.G., and Banerjee, S. (2019). Tubulin polymerization promoting protein, ringmaker, and MAP1B homolog futsch coordinate microtubule organization and synaptic growth. Frontiers in cellular neuroscience 13, 192.
Taylor, A.M., Shi, Q., and Bhat, M.A. (2018). Simultaneous ablation of neuronal neurofascin and ankyrin g in young and adult mice reveals age-dependent increase in nodal stability in myelinated axons and differential effects on the lifespan. eNeuro 5.
Shi, Q., Viswanadhapalli, S., Friedrichs, W.E., Velagapudi, C., Szyndralewiez, C., Bansal, S., Bhat, M.A., Choudhury, G.G., and Abboud, H.E. (2018a). Nox4 is a target for Tuberin deficiency syndrome. Scientific reports 8, 1-14.
Shi, Q., Saifetiarova, J., Taylor, A.M., and Bhat, M.A. (2018b). mTORC1 Activation by Loss of Tsc1 in Myelinating Glia Causes Downregulation of Quaking and Neurofascin 155 Leading to Paranodal Domain Disorganization. Frontiers in Cellular Neuroscience 12, 201.
Saifetiarova, J., Shi, Q., Paukert, M., Komada, M., and Bhat, M.A. (2018). Reorganization of destabilized nodes of ranvier in βIV spectrin mutants uncovers critical timelines for nodal restoration and prevention of motor paresis. Journal of Neuroscience 38, 6267-6282.
Niu, Z., Shi, Q., Zhang, W., Shu, Y., Yang, N., Chen, B., Wang, Q., Zhao, X., Chen, J., and Cheng, N. (2017). Caspase-1 cleaves PPARγ for potentiating the pro-tumor action of TAMs. Nature communications 8, 1-18.
Hu, Z., Shi, W., Riquelme, M.A., Shi, Q., Biswas, S., Lo, W.-K., White, T.W., Gu, S., and Jiang, J.X. (2017). Connexin 50 functions as an adhesive molecule and promotes lens cell differentiation. Scientific reports 7, 1-12.
Yao, Y., Shi, Q., Chen, B., Wang, Q., Li, X., Li, L., Huang, Y., Ji, J., and Shen, P. (2016). Identification of caspase-6 as a new regulator of alternatively activated macrophages. Journal of Biological Chemistry 291, 17450-17466.
Shi, Q., and Jiang, J.X. (2016). Connexin arrests the cell cycle through cytosolic retention of an E3 ligase. Molecular & Cellular Oncology 3, e1132119.
Zhao, Q.D., Viswanadhapalli, S., Williams, P., Shi, Q., Tan, C., Yi, X., Bhandari, B., and Abboud, H.E. (2015). NADPH oxidase 4 induces cardiac fibrosis and hypertrophy through activating Akt/mTOR and NFκB signaling pathways. Circulation 131, 643-655.
Thakur, S., Viswanadhapalli, S., Kopp, J.B., Shi, Q., Barnes, J.L., Block, K., Gorin, Y., and Abboud, H.E. (2015). Activation of AMP-activated protein kinase prevents TGF-β1–induced epithelial-mesenchymal transition and myofibroblast activation. The American journal of pathology 185, 2168-2180.
Shi, Q., Gu, S., Yu, X.S., White, T.W., Banks, E.A., and Jiang, J.X. (2015). Connexin controls cell-cycle exit and cell differentiation by directly promoting cytosolic localization and degradation of E3 ligase Skp2. Developmental cell 35, 483-496.
Feng, X., Qin, H., Shi, Q., Zhang, Y., Zhou, F., Wu, H., Ding, S., Niu, Z., Lu, Y., and Shen, P. (2014). Chrysin attenuates inflammation by regulating M1/M2 status via activating PPARγ. Biochemical pharmacology 89, 503-514.
Shi, Q., Padmanabhan, R., Villegas, C.J., Gu, S., and Jiang, J.X. (2011). Membrane topological structure of neutral system N/A amino acid transporter 4 (SNAT4) protein. Journal of Biological Chemistry 286, 38086-38094.
Liu, J., Vitorin, J.F.E., Weintraub, S.T., Gu, S., Shi, Q., Burt, J.M., and Jiang, J.X. (2011). Phosphorylation of connexin 50 by protein kinase A enhances gap junction and hemichannel function. Journal of Biological Chemistry 286, 16914-16928.
Shi, Q., Banks, E.A., Yu, X.S., Gu, S., Lauer, J., Fields, G.B., and Jiang, J.X. (2010). Amino acid residue Val362 plays a critical role in maintaining the structure of C terminus of connexin 50 and in lens epithelial-fiber differentiation. Journal of Biological Chemistry 285, 18415-18422.
Chen, T., Wang, Q., Cui, J., Yang, W., Shi, Q., Hua, Z., Ji, J., and Shen, P. (2005). Induction of apoptosis in mouse liver by microcystin-LR: a combined transcriptomic, proteomic, and simulation strategy. Molecular & Cellular Proteomics 4, 958-974.
Shi, Q., Cui, J., Zhang, J., Kong, F., Hua, Z., and Shen, P. (2004). Expression modulation of multiple cytokines in vivo by cyanobacteria blooms extract from Taihu Lake, China. Toxicon 44, 871-879.