Lander, Arthur D. - University of California, Irvine - Department of Developmental and Cell Biology

研究领域

Signaling & morphogenesis – The Lander lab is interested in the molecular mechanisms by which cells communicate. We focus on two kinds of pathways–those involving growth factors and their receptors, and those involving molecules of the extracellular matrix and their receptors. We study these pathways in the context of both mammalian (mouse) development and cancer biology, since growth control and cell-matrix interactions are critical to both processes. We also focus on cells of the nervous system, to understand why the growth that occurs during developing often fails to recur after injury (e.g. spinal cord injury). We are able to work in such a wide range of areas by (1) emphasizing fundamental aspects of cellular communication that have broad applications, and (2) utilizing approaches such as transgenic and “knockout” mice, that enable the roles and effects of molecules to be studied in the context of an entire organism. One group of projects in the lab concerns “co-receptors”, cell-surface molecules that regulate the interaction between soluble growth factors and their cell-surface receptors. We have identified a novel co-receptor for BMPs (bone morphogenetic proteins) and are studying the roles of Heparan Sulfate Proteoglycans (HSPGs) as co-receptors for a variety of growth factors, including those that drive tumor development and pattern the developing nervous system. We have used “knockout” technology to generate mice that are mutant for particular HSPGs, and are also working with mice that are mutant for some of the biosynthetic enzymes required to make HSPGs. We are also using modeling approaches to understand how HSPGs influences the kinetic parameters of growth factor-receptor interaction. Another area of investigation is the role of Chondroitin Sulfate Proteoglycans as scaffolding molecules that immobilize secreted signaling molecules. We study these in the developing brain, where they appear to play a role in localizing the molecules that guide growing axons. Another topic concerns a phenomenon called integrin activation, in which cells regulate the efficacy of their integrins, the major cells surface receptors for the extracellular matrix. We have obtained evidence that a decline in integrin activation accounts for some of the inability of mature central nervous system neurons to re-grow their axons after injury. We are using viral vectors to introduce genes into neurons of adult animals, in an attempt to reverse this decline.

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Chien, R., D.A. Newkirk, Y.-Y. Chen, W. Zeng, J. Biesinger, E. Flowers, N. Infante, S. Kawauchi, R. Santos, A.L. Calof, A.D. Lander, X. Xie and K. Yokomori (201X). The effect of Nipbl haploinsufficiency on genome-wide cohesin binding and gene expression. In preparation. Kunche, S., H. Yan, A.D. Lander, J.S. Lowengrub and A.L. Calof (201X) Feedback, lineages and de novo morphogenesis. In preparation for Physical Biology. Lo, W.C., S. Zhou, F.Y.M. Wan, A.D. Lander and Q. Nie (201X) Robust and Precise Morphogen-mediated Patterning: Tradeoffs, Constraints, and Mechanisms. In preparation. McHale, P. and A.D. Lander (201X) Role of symmetric stem cell divisions in delaying mutation accumulation. In preparation. Srinivasan, S., J.S. Hu, D.S. Currle, W.B. Hayes, A.D. Lander and E.S. Monuki (201X) Cell-intrinsic positive feedback driven by antagonistic extracellular signals as a basis for ultrasensitivity and developmental border formation. In revision. English, A.W., Y.-H. Jen, A. Mulligan, M.J. Sabatier, H. Saiyed, G. Schwartz, J. Spector, and A.D. Lander (200X) Axon regeneration after peripheral nerve injury is enhanced in syndecan and glypican knockout mice. In revision. Lander, A.D. (2013) How Cells Know Where They Are. Science. 339, 923-927. Konstorum, A., Sprowl, S.A., Lander, A.D., Waterman, M.L., Lowengrub, J.S. (2013) Elaboration of a multispecies model of solid tumor growth with tumor-host interactions. Proc. 3rd Int. Conf. Appl. Nonlinear Dynamics, Seattle, WA, Springer Verlag. Schilling T.F., Q. Nie and A.D. Lander (2012) Dynamics and precision in retinoic acid morphogen gradients. Curr Opin Genet Dev. doi:pii: S0959-437X(12)00142-6. 10.1016/j.gde.2012.11.012. [Epub ahead of print]. PMID: 23266215 Palmer, R., J. McGeary, S. Francazio, A. Heath., A.D. Lander, B. Raphael, V. Knopik. (2012) The Genetics of Alcohol Dependence: Advancing Towards Systems-based Approaches. Drug and Alcohol Dependence, July 31. dx.doi.org/10.1016/j.drugalcdep.2012.07.005, Epub ahead of print. PMID:22854292. PMCID: PMC3470479