The overarching aim of the Center is to provide a systems-level understanding for cellular decision-making focusing on the interrelated processes of cell proliferation, migration, and differentiation. Particularly, we will be focusing on how to develop and validate models that range from molecular single cell mechanisms to collective cell behavior. The center includes a research component with three synergistic projects, cores that will enrich systems biology research in Stanford, as well as an education component focusing on training graduate student and postdoctoral fellows in this emerging new field. We will also have an outreach effort to disseminate data sets and models and to invite researchers to participate in summer courses as well as to train in systems biology in Stanford. In the proposed research, we will focus on Collective Cell Proliferation by focusing on Xenopus laevis embryos and on primary human umbilical vein endothelial cells using novel biosensors developed in the participating laboratories. Our effort to understand Collective Cell Migration wil focus on mechanical models for collective migration based on novel insights into the propagation of force in 2-dimensional cell sheets. In our third effort to understand Collective Cel Differentiation we will be focusing on learning the rules by which cells collectively transition from proliferative to differentiated states using human induced pluripotent stem (IPS) cells, granule neuron precursors (GNP), adipocytes, and drosophila wing epithelial cells as models. Since neighboring cells tend to differentiate in a correlated fashion, we will seek to understand how cells coordinate differentiation by testing whether secreted factors and direct cell contact contribute to collective differentiation decisions. These research efforts will be augmented by the development of new perturbation and biosensor technologies that will enable us to validate models for these processes. The investigated biological projects share common regulatory designs, adding significant synergies that will enhance the change that significant new advances will be made in the proposed Center.
The proposed work will elucidate fundamental regulatory mechanisms how cells divide, move and differentiate. These processes are critical in cancer, neurodegeneration and in many other diseases. Insights into the regulation of these processes may lead, with a longer term time horizon, to new types of therapies for these diseases.
|Ferrell Jr, James E; Ha, Sang Hoon (2014) Ultrasensitivity part I: Michaelian responses and zero-order ultrasensitivity. Trends Biochem Sci 39:496-503|
|Rakhit, Rishi; Navarro, Raul; Wandless, Thomas J (2014) Chemical biology strategies for posttranslational control of protein function. Chem Biol 21:1238-52|
|Ahrends, Robert; Ota, Asuka; Kovary, Kyle M et al. (2014) Controlling low rates of cell differentiation through noise and ultrahigh feedback. Science 344:1384-9|
|Yamazoe, Sayumi; McQuade, Lindsey E; Chen, James K (2014) Nitroreductase-activatable morpholino oligonucleotides for in vivo gene silencing. ACS Chem Biol 9:1985-90|
|Matis, Maja; Russler-Germain, David A; Hu, Qie et al. (2014) Microtubules provide directional information for core PCP function. Elife 3:e02893|
|Niewiadomski, Pawel; Kong, Jennifer H; Ahrends, Robert et al. (2014) Gli protein activity is controlled by multisite phosphorylation in vertebrate Hedgehog signaling. Cell Rep 6:168-81|
|Ferrell Jr, James E; Ha, Sang Hoon (2014) Ultrasensitivity part III: cascades, bistable switches, and oscillators. Trends Biochem Sci 39:612-8|
|Regot, Sergi; Hughey, Jacob J; Bajar, Bryce T et al. (2014) High-sensitivity measurements of multiple kinase activities in live single cells. Cell 157:1724-34|
|Gelens, Lendert; Anderson, Graham A; Ferrell Jr, James E (2014) Spatial trigger waves: positive feedback gets you a long way. Mol Biol Cell 25:3486-93|
|Karr, Jonathan R; Phillips, Nolan C; Covert, Markus W (2014) WholeCellSimDB: a hybrid relational/HDF database for whole-cell model predictions. Database (Oxford) 2014:|