School of Molecular and Cellular Biology
University of Illinois at Urbana-Champaign
419 Roger Adams Laboratory
600 South Mathews
Urbana, IL 61801
Imaging, Neurobiology, Optogenetics, Signal Transduction
*Position available: The Zhang laboratory welcomes motivated students and postdoctoral fellows in biochemistry, biophysics, cell biology, neuronal biology to join the group. Please contact Kai Zhang (firstname.lastname@example.org) with a description of your scientific research interests.*
The Zhang group studies how signal transduction regulates cell fate determination and how normal signaling processes are compromised in disease conditions. Using live cell imaging and optogenetic control of signal transduction, we observe and perturb signaling modules to define cellular responses. Our major goal is to gain insight into signaling mechanisms that regulate critical cellular functions such as cell proliferation, differentiation, migration, and apoptosis and to apply the insight to understanding and treating neurological disorders.
1. Spatiotemporal control of growth-factor signal transduction by optogenetics
Cells are constantly making decisions in response to their environments. Intracellular signal transduction transmits external stimuli into the cell interior and regulates transcription and translation. Growth factor-mediated signal transduction regulates a wide spectrum of cellular functions such as cell proliferation, differentiation, migration, and apoptosis. Dysregulated growth factor signaling has been observed in various diseases including cancers or neurological disorders. Intriguingly, different growth factors trigger distinct cellular functions via activation of similar downstream signaling cascades such as the mitogen activated protein kinase (MAPK), phosphoinositide 3-kinase (PI3K)-AKT, and phospholipase C (PLC). Consequently, a central question in growth-factor mediated signal transduction is how the same set of signaling cascades elicits such diverse yet specific cellular outcomes. Previous research has suggested that cells employ spatiotemporal regulation of their signaling cascades to convey specificity of cell fate determination. For instance, epidermal growth factor (EGF) triggers a transient MAPK activation and induces cell proliferation; nerve growth factor (NGF) triggers a sustained MAPK activation and induces cell differentiation. Directed cell migration is driven by asymmetric subcellular activation of actin dynamics. Conventional pharmacological and genetic approaches have continuously expanding our knowledge base of signaling components involved in signaling networks. These approaches, however, lack the resolution of spatial and temporal control. A better understanding of signaling mechanisms therefore calls for new tools that can precisely control intracellular signaling in both space and time.
Optogenetics combines the power of light and genetics and enables precise spatial and temporal control of individual signaling cascades. Our previous work used light to control the MAPK signaling pathway and quantitatively revealed the kinetic effect of the MAPK signaling on cell differentiation. In the long term, we aim to 1) extend optogenetic modules for activating other growth factor signaling pathways, 2) dissect how spatiotemporal regulation of growth-factor signal pathways determine cell fate, and 3) develop new optogenetic tools using protein engineering, computation, and genetic screening.
2. Axonal transport in neurological disorders
Neurons are the most polarized cell types, extending processes 10,000 times the size of their cell bodies. In such a polarized cell, Brownian diffusion is not sufficient to drive efficient communications across the whole neuron cell. For a small molecule to diffuse from the hand to the brain, it will take about 30 years! Instead, communication between different parts of neuronal cells requires active transport. Cargoes containing signaling molecules or newly synthesized proteins are transported along the cytoskeletal tracks of axons, very similar to the vehicle transport on highways. Defective axonal transport has been observed in neurological disorders such as Alzheimer’s disease, Parkinson’s disease, Amyotrophic Lateral Sclerosis (ALS), and Charcot-Marie-Tooth neuropathy, to name a few.
The Zhang group studies the neurotrophic signaling pathway that primarily regulates neuronal differentiation and survival. Our previous work has shown that axonal transport can be either slowed down or accelerated in neurological disorders. We use compartmentalized microfluidic devices to spatially segregate and control the chemical environment of axons and cell bodies. We use live cell imaging to track the axonal transport of fluorescently labeled cargos. Our long term goal is to determine how axonal transport is affected by specific neuronal phenotypes and how manipulation of axonal transport may rescue these phenotypes.
B.S. 2002 University of Science and Technology of China (USTC), China
Ph.D. 2008 University of California, Berkeley
Postdoc. 2009-2014 Stanford University
Additional Campus Affiliations
S. K. Misra, I. Srivastava, J.S. Khamo, V. V. Krishnamurthy, D. Sar, A. S. Schwartz-Duval, J. A. N. T. Soares, K. Zhang* and D. Pan* “Carbon Dots with Induced Surface Oxidation Permits Imaging at Single-Particle Level for Intracellular Studies”, Nanoscale, 2018 (DOI: 10.1039/c8nr04065f).
V. V. Krishnamurthy, K. Zhang “Chemical physics in living cells – using light to visualize and control intracellular signal transduction” Chinese Journal of Chemical Physics, 2018 (DOI:10.1063/1674-0068/31/cjcp1806152).
K. Sung, L. F. Ferrari, W. Yang, C. Chung, X. Zhao, Y. Gu, S. Lin, K. Zhang, B. Cui, M. L. Pearn, M. T. Maloney, W. C. Mobley, J. D. Levine and C. Wu ” Swedish Nerve Growth Factor Mutation (NGFR100W) Defines a role for TrkA and p75NTR in Nociception”, Journal of Neuroscience, 2018 38(14): 3394-3413 (DOI: 10.1523/JNEUROSCI.1686-17.2018).
J.S. Khamo, V. V. Krishnamurthy, P. Mondal, S. R. Sharum, and K. Zhang* “Applications of optobiology in intact cells and multi-cellular organisms”, Journal of Molecular Biology, 2017, 429, 2999-3017. (DOI: 10.1016/j.jmb.2017.08.015).
V. V. Krishnamurthy, A. J. Turgeon, J.S. Khamo, P. Mondal, S. R. Sharum, W. Mei, J. Yang*, and K. Zhang* “Light-mediated reversible modulation of the mitogen-activated protein kinase pathway during cell differentiation and Xenopus embryonic development”, J. Vis. Exp., 2017, 124, e55823.
P. Mondal, J. S. Khamo, V. V. Krishnamurthy, Q. Cai, and K. Zhang* “Drive The Car(go)s—New Modalities to Control Cargo Trafficking in Live Cells” Front. Mol. Neurosci.2017, 10, 4. (DOI: 10.3389/fnmol.2017.00004).
V. V. Krishnamurthy, K. Zhang* ” Simultaneous removal of multiple DNA segments by polymerase chain reactions” Methods Mol Biol., Synthetic DNA, Ed R. Hughes. (Springer New York) 2017, 1472, 193-203. (DOI: 10.1007/978-1-4939-6343-0_15).
V. V. Krishnamurthy, J.S. Khamo, W. Mei, A. J. Turgeon, H. M. Ashraf, P. Mondal, D. B. Patel, N. Risner, E. E. Cho, J. Yang*, and K. Zhang* “Reversible optogenetic control of kinase activity during differentiation and embryonic development” Development, 2016, 143, 4085-4094. (DOI: 10.1242/dev.140889).
V. V. Krishnamurthy, J. S. Khamo, E. Cho, C. Schornak, and K. Zhang* “Multiplex gene removal by two-step polymerase chain reactions”, Analytical Biochemistry, 2015, 481, 7-9. (DOI: 10.1016/j.ab.2015.03.033).
Zhang K* and Cui B* (2015) Optogenetic control of intracellular signaling pathways, Trend in Biotechnology, 33, 92-100.
Ong Q, Guo S, Zhang K, and Cui B (2015) U0126 Protects Cells against Oxidative Stress Independent of Its Function as a MEK Inhibitor, ACS Chem. Neurosci., 6,130–137.
Zhang K, Cui B (2014) Lighting up FGFR Signaling, Chemistry & Biology, 21, 806-808.
Zhang K, Duan L, Ong Q, Lin Z, Varman P, Sung K, Cui B (2014) Light-Mediated Kinetic Control Reveals the Temporal Effect of the Raf/MEK/ERK Pathway in PC12 Cell Neurite Outgrowth, PLoS ONE 9 (3):e92917
Zhang K, Fishel Ben Kenan R, Osakada Y, Xu W, Sinit RS, Chen L, Zhao X, Chen JY, Cui B, Wu C (2013) Defective Axonal Transport of Rab7 GTPase Results in Dysregulated Trophic Signaling, J Neurosci 33 (17):7451-7462
Xie W, Zhang K, Cui B (2012) Functional characterization and axonal transport of quantum dot labeled BDNF, Integr Biol 4 (8):953-960
Zhang K, Osakada Y, Xie W, Cui B (2011) Automated image analysis for tracking cargo transport in axons, Microsc Res Tech 74 (7):605-613
Vossel KA, Zhang K, Brodbeck J, Daub AC, Sharma P, Finkbeiner S, Cui B, Mucke L (2010) Tau reduction prevents Abeta-induced defects in axonal transport, Science 330 (6001):198
Zhang K, Osakada Y, Vrljic M, Chen L, Mudrakola HV, Cui B (2010) Single-molecule imaging of NGF axonal transport in microfluidic devices, Lab Chip (10):2566-2573
Mudrakola HV, Zhang K, Cui B (2009) Optically resolving individual microtubules in live axons, Structure 17 (11):1433-1441
Zhang K, Chang H, Fu AH, Alivisatos AP, and Yang H (2006) Continuous Distribution of Emission States from Single CdSe/ZnS quantum dots, Nano Lett. 6(4), 843-847.
(* corresponding author)
Zhu, F., Fang, Y., Zhang, K., Chang, K., Cao, H., Jiang, Z., & Wu, M. (2023). Unified and Incremental SimRank: Index-free Approximation with Scheduled Principle. IEEE Transactions on Knowledge and Data Engineering, 35(3), 3195-3210. https://doi.org/10.1109/tkde.2021.3111734
Fan, H., Barnes, C., Hwang, H., Zhang, K., & Yang, J. (2022). Precise modulation of embryonic development through optogenetics. Genesis (United States), 60(10-12), Article e23505. https://doi.org/10.1002/dvg.23505
Qiu, K., Zou, W., Fang, H., Hao, M., Mehta, K., Tian, Z., Guan, J. L., Zhang, K., Huang, T., & Diao, J. (2022). Light-activated mitochondrial fission through optogenetic control of mitochondria-lysosome contacts. Nature communications, 13(1), Article 4303. https://doi.org/10.1038/s41467-022-31970-5
Skeeters, S. S., Camp, T., Fan, H., & Zhang, K. (2022). The expanding role of split protein complementation in opsin-free optogenetics. Current Opinion in Pharmacology, 65, Article 102236. https://doi.org/10.1016/j.coph.2022.102236
Wang, Q., Huang, X., Su, Y., Yin, G., Wang, S., Yu, B., Li, H., Qi, J., Chen, H., Zeng, W., Zhang, K., Verkhratsky, A., Niu, J., & Yi, C. (2022). Activation of Wnt/β-catenin pathway mitigates blood-brain barrier dysfunction in Alzheimer's disease. Brain, 145(12), 4474-4488. https://doi.org/10.1093/brain/awac236