Single cell and collective cell migration are fundamental processes that enable human development, immune responses and wound healing while also playing a key function in cancer progression. Our overall goal in this project is to understand the fundamental molecular and cellular mechanisms of how single cells and groups of human cells migrate. We will be focusing on two in vitro cell models, human umbilical vasculature endothelial cells (HUVEC) to study collective directed migration in response to growth factor and a cell model for neutrophils, differentiated HL-60 cells, to investigate single cell chemotaxis. These model systems were chosen since they allow us to use automated imaging of important functional migration parameters to explore the role of a large numbers of migration related genes using siRNAs knockdown and to perform a phenotypic classification. Our project is taking a systems approach, using small interference RNAs to perturb different parts of the cell migration machinery as well as computational modeling approaches. We are also employing rapid chemical perturbation methods of the PI3K and other pathways that our laboratory developed as well as high resolution fluorescent imaging using biosensors and markers for cell migration. By perturbing and monitoring local signaling events, we will be exploring different hypotheses of how cells polarize, steer their front and migrate with the goal to generate a quantitative molecular and mechanistic model for directed migration in these cell models. Insights into new regulators of migration and the roles that different regulators play in the overall endothelial and leukocyte migration processes will likely lead to the identification of new drug targets relevant for vasculature, immune diseases or cancer.

Public Health Relevance

Single cell and collective cell migration are fundamental processes that enable human development, immune responses and wound healing while also playing a necessary function in cancer progression. Our overall goal in this grant is to understand the key molecular and cellular mechanisms of how single cells and groups of human cells migrate.

Agency
National Institute of Health (NIH)
Institute
National Institute of General Medical Sciences (NIGMS)
Type
Research Project (R01)
Project #
5R01GM063702-12
Application #
8450790
Study Section
Cellular Signaling and Regulatory Systems Study Section (CSRS)
Program Officer
Nie, Zhongzhen
Project Start
2002-04-01
Project End
2014-03-31
Budget Start
2013-04-01
Budget End
2014-03-31
Support Year
12
Fiscal Year
2013
Total Cost
$331,259
Indirect Cost
$122,993
Name
Stanford University
Department
Biology
Type
Schools of Medicine
DUNS #
009214214
City
Stanford
State
CA
Country
United States
Zip Code
94305
Habib, Shukry J; Chen, Bi-Chang; Tsai, Feng-Chiao et al. (2013) A localized Wnt signal orients asymmetric stem cell division in vitro. Science 339:1445-8
Tsai, Feng-Chiao; Meyer, Tobias (2012) Ca2+ pulses control local cycles of lamellipodia retraction and adhesion along the front of migrating cells. Curr Biol 22:837-42
Vitorino, Philip; Hammer, Mark; Kim, Jongmin et al. (2011) A steering model of endothelial sheet migration recapitulates monolayer integrity and directed collective migration. Mol Cell Biol 31:342-50
Bandara, Samuel; Schloder, Johannes P; Eils, Roland et al. (2009) Optimal experimental design for parameter estimation of a cell signaling model. PLoS Comput Biol 5:e1000558
Vitorino, Philip; Meyer, Tobias (2008) Modular control of endothelial sheet migration. Genes Dev 22:3268-81
Inoue, Takanari; Meyer, Tobias (2008) Synthetic activation of endogenous PI3K and Rac identifies an AND-gate switch for cell polarization and migration. PLoS One 3:e3068
Brandman, Onn; Meyer, Tobias (2008) Feedback loops shape cellular signals in space and time. Science 322:390-5
Gong, Delquin; Pomerening, Joseph R; Myers, Jason W et al. (2007) Cyclin A2 regulates nuclear-envelope breakdown and the nuclear accumulation of cyclin B1. Curr Biol 17:85-91
Galvez, Thierry; Teruel, Mary N; Heo, Won Do et al. (2007) siRNA screen of the human signaling proteome identifies the PtdIns(3,4,5)P3-mTOR signaling pathway as a primary regulator of transferrin uptake. Genome Biol 8:R142
Suh, Byung-Chang; Inoue, Takanari; Meyer, Tobias et al. (2006) Rapid chemically induced changes of PtdIns(4,5)P2 gate KCNQ ion channels. Science 314:1454-7

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