Tian, Lin - University of California, Davis - Department of Biochemistry and Molecular Medicine

研究领域

The goal of our research is to invent new molecular tools for analyzing and engineering functional neural circuits. We also leverage these tools, combined with optical imaging techniques, to study molecular mechanisms of neurological disorders at system level and to empower searching for novel therapeutic treatments. One of the primary challenges in neuroscience is to link complex neural phenomena to the structure and function of their composite neural circuits. Addressing this problem requires a thorough understanding of patterns of neural activity, and the ability to relate this to physiological processes, behavior and disease states. An essential step towards this goal is the simultaneous recording of neural activity in large, defined populations, ideally in intact circuitry. Traditional electrophysiological approaches provide excellent sensitivity and temporal resolution, but are limited in the number of cells that can be recorded simultaneously. Fluorescent protein based biosensors can transfer changes in neural state (e.g. membrane potential or essential ion flux or enzyme activity) to fluorescence observables. They are genetically encoded, and can thus be used to label large populations of defined cell types and/or sub-cellular compartments. Combined with modern fluorescence imaging techniques, these probes allow us observe and track how neural networks are established or modified in time and space and find out what goes wrong in diseases. Our lab used a variety of techniques (computational protein engineering, rational design, molecular evolution, chemical synthesis) to develop genetically encoded imaging probes, such as calcium indicators, neurotransmitter sensors and kinase sensors. We also explore strategies for better targeting these sensors to small compartments in the nervous system, such as axon terminals, and for longer expression with reduced cytotoxicity in vivo. Chemical probes are also essential tools in biology for measuring and manipulating cellular properties. Evan wit high molecular specificity, however, their application in complex biological environments is frequency limited by poor cellular specificity. Our previous research has demonstrated a straightforward approach for the identification of orthogonal ester-esterase pairs that are stable to endogenous esterase activity and can be directed to specific cell types. We will utilize different chemistries in future work to develop tissue-specific probes for drug or metabolite localization and activity in cells, tissues, or model organisms. We also integrate our imaging probes to induced pluripotent stem cells (iPSCs)-derived neurons and glias to create a platform for studying psychiatric diseases in vitro. Such cultured human neuronal networks will enable us to visualize how the precise, guided communication in neurons develops, and how it breaks down in diseases. With this system we can test a library of drugs to identify ones that can correct the communications defects in a patient-specific manner; such a drug screening would not be possible on living patients. My research program will provide interdisciplinary trainings for graduate students and postdoc fellows.

近期论文

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Y. Gao, G. Broussard, A. Haque, A. Revzin, and L. Tian, "Functional imaging of neuron-astrocyte interactions in a compartmentalized microfluidic device," Nature: Microsystems & Nanoengineering 2, (2016). Y. Wang, G. Shi, D. J. Miller, G. Broussard, L. Tian*, and G. Yu*, "FASP: A machine learning approach to functional astrocyte phenotyping from time-lapse calcium imaging data," IEEE 13th International Symposium on Biomedical Imaging (ISBI), 351-354 (2016). *equal contribution Y. Zhi, G. Shi, D. J. Miller, G. Broussard, L. Tian*, and G. Yu, "Graphical Time Warping for Joint Alignment of Multiple Curves", paper 1815, Neural Information Processing Systems, 2016 R. Liang, G. Broussard, and L. Tian, "Imaging chemical neurotransmission with genetically encoded fluorescent sensors," ACS chemical neuroscience 6, 84-93 (2015). L. Qin, M. Fan, D. Candas, G. Jiang, S. Papadopoulos, L. Tian, G. Woloschak, D. J. Grdina, and J. J. Li, "CDK1 enhances mitochondrial bioenergetics for radiation-induced DNA repair," Cell reports 13, 2056-2063 (2015). G. Broussard, R. Liang, & L. Tian, "Monitoring activity in neural circuits with genetically encoded indicators," Frontiers in molecular neuroscience 7, 97 (2014). J. Macklin, J. Akerboom, E. R. Schreiter, L. Tian, R. Patel, V. Iyer, B. Karsh, J. Colonell, and T. D. Harris, "Two Photon Photophysics of Fluorescent Protein Calcium Indicators," Biophysical Journal 104, 682a (2013). J. Akerboom, N. Carreras Calderon, L. Tian et al, "Genetically encoded calcium indicators for multi-color neural activity imaging and combination with optogenetics," Frontiers in molecular neuroscience 6, 2 (2013). J. Marvin, B. G. Borghuis, L. Tian et al. "An optimized fluorescent probe for visualizing glutamate neurotransmission," Nature methods 10, 162-170 (2013). L. Tian, Y. Yang, L. M. Wysocki, A. C. Arnold, A. Hu, B. Ravichandran, S. M. Sternson, L. L. Looger, and L. D. Lavis, "Selective esterase-ester pair for targeting small molecules with cellular specificity", Proceedings of the National Academy of Sciences 109, 4756-4761 (2012). J. Akerboom, T.-W. Chen, T. J. Wardill, L. Tian et al. Optimization of a GCaMP calcium indicator for neural activity imaging. The Journal of neuroscience 32, 13819-13840 (2012). D. C. Huber, D. A. Gutnisky, S. Peron, D. H. O‚ Connor, J. S. Wiegert, L. Tian, T. G. Oertner, L. L. Looger, and K. Svoboda, "Multiple dynamic representations in the motor cortex during sensorimotor learning," Nature 484, 473-478 (2012). L. Tian, S.A. Hires, & L.L. Looger, "Imaging neuronal activity with genetically encoded calcium indicators," Cold Spring Harbor Protocols (2012) J. Akerboom, L. Tian, J. Marvin, & L.L. Looger, "Engineering and application of genetically encoded calcium indicators," Genetically Encoded Functional Indicators 125-147 (2012). L. Petreanu, D. A. Gutnisky, D. Huber, N.-l. Xu, D. H. O‚ Connor, L. Tian, L. L. Looger, and K. Svoboda, "Activity in motor-sensory projections reveals distributed coding in somatosensation," Nature 489, 299-303 (2012). H.A. Zariwala, B. G. Borghuis, T. M. Hoogland, L. Madisen, L. Tian, C. I. De Zeeuw, H. Zeng, L. L. Looger, K. Svoboda, and T.-W. Chen, "A Cre-dependent GCaMP3 reporter mouse for neuronal imaging in vivo," The Journal of Neuroscience 32, 3131-3141 (2012). B.G. Borghuis, L. Tian, Y. Xu, S. S. Nikonov, N. Vardi, B. V. Zemelman, and L. L. Looger, "Imaging light responses of targeted neuron populations in the rodent retina," The Journal of Neuroscience 31, 2855-2867 (2011). T. Knopfel, M. Z. Lin, A. Levskaya, L. Tian, J. Y. Lin, and E. S. Boyden, "Toward the second generation of optogenetic tools," The Journal of Neuroscience 30, 14998-15004 (2010). D. A. Dombeck, C. D. Harvey, L. Tian, L. Looger, & D. W. Tank, "Functional imaging of hippocampal place cells at cellular resolution during virtual navigation," Nature neuroscience 13, 1433-1440 (2010). L. Tian, S. A. Hires, T. Mao, D. Huber, M. E. Chiappe, S. H. Chalasani, L. Petreanu, J. Akerboom, S. A. McKinney, E. R. Schreiter, C. I. Bargmann, V. Jayaraman, K. Svoboda, L. Looger, "Imaging neural activity in worms, flies and mice with improved GCaMP calcium indicators," Nature methods 6, 875-881 (2009). J. Akerboom, J. D. V. Rivera, M. M. R. Guilbe, L. Tian, S. A. Hires, J. S. Marvin, L. L. Looger, and E. R. Schreiter, "Crystal structures of the GCaMP calcium sensor reveal the mechanism of fluorescence signal change and aid rational design," Journal of biological chemistry 284, 6455-6464 (2009). S. A. Hires, L. Tian, & L. L. Looger, "Reporting neural activity with genetically encoded calcium indicators," Brain cell biology 36, 69-86 (2008). L. Tian, & L. L. Looger, "Genetically encoded fluorescent sensors for studying healthy and diseased nervous systems," Drug Discovery Today: Disease Models 5, 27-35 (2008). L. Tian, & Matouschek, A., "Where to start and when to stop," Nature structural & molecular biology 13, 668-670 (2006). L. Tian, R. A. Holmgren, & A. Matouschek, "A conserved processing mechanism regulates the activity of transcription factors Cubitus interruptus and NF-kB," Nature structural & molecular biology 12, 1045-1053 (2005).