Research Interests

Research in this laboratory encompasses several projects. We have a longstanding effort aimed at developing and characterizing fluorescent probes of membrane potential. Although this effort is continuing, we are now particularly focused on studies of the non-linear optical properties of the dyes, including second harmonic generation as an alternative to fluorescence as a probe of membrane potential. A second project is aimed at elucidating how electrical potentials may vary along neuronal surfaces and the cell physiological consequences of such heterogeneities. Among the consequences that have been suggested by our studies are directed neurite outgrowth and local sensitization of voltage-dependent ion channels. Quantitative digital imaging microscopy is combined with patch clamp recording in these studies and has revealed roles for intracellular calcium changes in the mechanisms of these phenomena. Finally, we are very excited about a project called the "Virtual Cell", in which we have created a framework for using computer simulation to explore cell biological mechanisms. The models are built naturally from experimental images of cell and subcellular structures combined with biochemical and electrophysiological data. Among the published ways we have used the “Virtual Cell” system are to explain the pattern of cytosolic calcium waves evoked by hormonal stimulation of a neuronal cell and the regulation of nucleocytoplasmic transport.

Honors, Awards, and Professional Activities

Phi Beta Kappa; NSF Trainee, 1969-73, Nehemiah Gittelson Medal; NIH Research Career Development Award, 1980-85; American Chemical Society; Biophysical Society; AAAS. Editorial Boards: Biophysical Journal, Journal of Fluorescence, Cell Biophysics & Biochemistry; Chair NIH MABS Study Section, 2004-2006; Boehringer Ingelheim Chair in Cell Sciences, 2007 - ; Elected to Connecticut Academy of Science and Engineering, 2008.

Selected Publications

De Lorimier RM, Smith JJ, Dwyer MA, Looger LL, Sali KM, Paavola CD, Rizk SS, Sadigov S, Conrad DW, Loew L and Hellinga HW. 2002. Construction of a fluorescent biosensor family. Protein Sci 11(11):2655-2675

Slepchenko B, Schaff JC, Carson JH, Loew LM. 2002. Computational cell biology: spatiotemporal simulation of cellular events. Annual Review of Biophysics & Biomolecular Structure 31:423-441.

Smith AE, Slepchenko BM, Schaff JC, Loew LM, Macara IG. 2002. Systems analysis of Ran transport. Science 295:488-491.

Loew LM, Campagnola PJ, Lewis A, Wuskell JP. 2002. Confocal and non-linear optical imaging of potentiometric dyes. In: Matsumoto B, editor. Methods in Cell Biology. Academic Press, Orlando, FL, 423-446.

Millard, A. C., P. J. Campagnola, W. Mohler, A. Lewis, and L. M. Loew. 2003. Second harmonic imaging microscopy. in Methods in Enzymology. Vol 361. G. Marriott and I. Parker, editors. Academic Press, San Diego. 47-69.

Asamoah OK, Wuskell JP, Loew LM, Bezanilla F. 2003. A fluorometric approach to local electric field measurements in a voltage-gated ion channel. Neuron 37(1):85-97.

Hucka M, Finney A, Sauro HM, Bolouri H, Doyle JC, Kitano H, Arkin AP, Bornstein BJ, Bray D, Cornish-Bowden A and others. 2003. The systems biology markup language (SBML): a medium for representation and exchange of biochemical network models. Bioinformatics 19(4):524-531.

Xu C, Loew LM. 2003. Activation of phospholipase C increases intramembrane electric fields in N1E-115 neuroblastoma cells. Biophys J 84:4144-4156.

Xu C, Loew LM. 2003. Surface potential measurements on biological membranes with voltage-sensitive dyes. Biophys J 84:2768-2780.

Xu, C., J. Watras, and L. M. Loew. 2003. Kinetic analysis of receptor activated phosphoinositide turnover. J. Cell Biol. 161:779-791.

Millard AC, Jin L, Lewis A, Loew LM. 2003. Direct measurement of the voltage sensitivity of second-harmonic generation from a membrane dye in patch-clamped cells. Optics Letters 28(14):1221-1223.

Slepchenko BM, Schaff J, Macara IG, Loew LM. 2003. Quantitative Cell Biology with the Virtual Cell. Trends in Cell Biology 13:570-576.

Campagnola P, Loew LM. 2003. Second-harmonic imaging microscopy for visualizing biomolecular arrays in cells, tissues and organisms. Nature Biotechnology 21(11):1356-1360.

Millard AC, Jin L, Wei M-d, Wuskell JP, Lewis A, Loew LM. 2004. Sensitivity of second harmonic generation from styryl dyes to trans-membrane potential. Biophysical Journal 86:1169-76.

Obaid AL, Loew LM, Wuskell JP, Salzberg BM. 2004. Novel naphthylstyryl-pyridinium potentiometric dyes offer advantages for neural network analysis. J. Neurosci. Methods 134:179-90.

Wagner J, Fall CP, Hong F, Sims CE, Allbritton NL, Fontanilla RA, Moraru II, Loew LM, Nuccitelli R. 2004. A wave of IP3 production accompanies the fertilization Ca2+ wave in the egg of the frog, Xenopus laevis: theoretical and experimental support. Cell Calcium 35:433-47.

Schaff, J. C., J. Carson and L. M. Loew. 2004. “Method for modeling cellular structure and function,” United States Patent 6,708,141.

Fall, CP, Wagner, JM, Loew LM, Nuccitelli , R. 2004. Cortically Restricted Production of IP3 Leads to Propagation of the Ferilization Ca2+ Wave Along the Cell Surface in a Model of the Xenopus Egg. J. Theor. Biol., 231:487-496.

Novak IL, Slepchenko BM, Mogilner A, Loew LM. 2004. Cooperativity between cell contractility and adhesion. Phys Rev Lett 93:268109-1-4.

Mayya, V., and L.M. Loew. 2005. STAT module can function as a biphasic amplitude filter. Systems Biology. 2:43-52.

Moraru, I.I., and L.M. Loew. 2005. Intracellular signaling: spatial and temporal control. Physiology, 20: 169-179.

Millard, A.C., M. Terasaki, and L.M. Loew. 2005. Second harmonic imaging of exocytosis at fertilisation. Biophys. J., 88:L46-8.

Jin, L., A.C. Millard, J.P. Wuskell, H.A. Clark, and L.M. Loew. 2005. Cholesterol enriched lipid domains can be visualized by di-4-ANEPPDHQ with linear and non-linear optics. Biophys. J. 89: L4-6.

Watras, J., C.C. Fink, and L.M. Loew. 2005. Endogenous Inhibitors of InsP3-induced Ca2+ Release in Neuroblastoma cells. Brain Research. 1055:60-72.

Hernjak, N., B. M. Slepchenko, K. Fernald, C. C. Fink, D. Fortin, I. I. Moraru, J. Watras, and L. M. Loew, 2005. Modeling and analysis of calcium signaling events leading to long-term depression in cerebellar Purkinje cells. Biophys. J. 89:3790-3806.

Milojkovic B.A., Wuskell J., Loew L. M., and Antic S.A., 2005. Initiation of sodium spikelets in basal dendrites of neocortical pyramidal neurons. J. Memb. Biol. 208:155-169.

Millard, A.C., Jin, L., Wuskell, J.P. Boudreau, D. M. Lewis, A. and Loew, L. M., 2005. Wavelength- and Time-Dependence of Potentiometric Non-linear Optical Signals from Styryl Dyes. J. Memb. Biol. 208:103-111.

Matiukas, A., B. G. Mitrea, A. M. Pertsov, J. P. Wuskell, M.-d. Wei, J. Watras, A. C. Millard, and L. M. Loew. 2005. New Near Infrared Optical Probes of Cardiac Electrical Activity. Am. J. Physiol. 290:H2633-2643.

Wuskell, J. P., D. Boudreau, M. D. Wei, L. Jin, R. Engl, R. Chebolu, A. Bullen, K. D. Hoffacker, J. Kerimo, L. B. Cohen, M. R. Zochowski, and L. M. Loew. 2006. Synthesis, spectra, delivery and potentiometric responses of new styryl dyes with extended spectral ranges. J. Neurosc. Meth. 151:200-15.

Jin, L., A. C. Millard, J. P. Wuskell, X. Dong, D. Wu, H. A. Clark and L. M. Loew. 2006. Characterization and Application of a New Optical Probe for Membrane Lipid Domains. Biophys. J., 90:2563-75.

Yan, P., A.C. Millard, M. Wei, and L.M. Loew. 2006. Unique Contrast Patterns from Resonance-Enhanced Chiral SHG of Cell Membranes. J. Am. Chem. Soc. 128:11030-11031.

Moraru, I.I., J.C. Schaff, and L.M. Loew. 2006. Think simulation – think experiment: the Virtual Cell paradigm. In 2006 Winter Simulation Conference. Vol. 38. L.F. Perrone, F.P. Wieland, J. Liu, B.G. Lawson, D.M. Nicol, and R.M. Fujimoto, editors. Winter Simulation Conference, Monterey, CA. 1713-1719.

Loew, L.M. 2007. Where does all the PIP2 come from? Journal of Physiology. 582:945-951.

Millard, A.C., L. Jin, and L.M. Loew. 2007. Second harmonic generation imaging microscopy with a high power ultrafast fiber laser. Proceedings of SPIE. 5714:92-98.

Teisseyre, T.Z., A.C. Millard, P. Yan, J.P. Wuskell, M.-d. Wei, A. Lewis, and L.M. Loew. 2007. Non-linear Optical Potentiometric Dyes Optimized for Imaging with 1064 nm Light. J. Biomed. Opt. 12:044001-1 - 044001-8.

Zhou, W.-L., Y. Ping, J.P. Wuskell, L.M. Loew, and S.D. Antic. 2007. Intracellular long wavelength voltage-sensitive dyes for studying the dynamics of action potentials in axons and thin dendrites. J. Neurosci. Methods. 164:225-239.

Matiukas, A., B.G. Mitrea, M. Qin, A.M. Pertsov, A.G. Shvedko, M.D. Warren, A.V. Zaitsev, J.P. Wuskell, M.-d. Wei, J. Watras, and L.M. Loew. 2007. Near Infrared Voltage Sensitive Fluorescent Dyes Optimized for Optical Mapping in Blood-Perfused Myocardium. Heart Rhythm, 4:1441-1451.

Zhou, W.L., P. Yan, J.P. Wuskell, L.M. Loew, and S.D. Antic. 2008. Dynamics of action potential backpropagation in basal dendrites of prefrontal cortical pyramidal neurons. Eur J Neurosci. 27:923-936

Patents

Sapia, M. A., J. C. Schaff, I. R. Greenshields, L. M. Loew, and F. R. Morgan (2000) “Method and apparatus for three-dimensional deconvolution of optical microscope images,” United States Patent 6,166,853.

Schaff, J. C., J. Carson and L. M. Loew (2001) “Method and apparatus for modeling cell structure and function,” United States Patent 6,219,440.

Schaff, J. C., J. Carson and L. M. Loew (2004) “Method for modeling cellular structure and function,” United States Patent 6,708,141.