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 #
5R01GM063702-11
Application #
8245092
Study Section
Cellular Signaling and Regulatory Systems Study Section (CSRS)
Program Officer
Deatherage, James F
Project Start
2002-04-01
Project End
2014-03-31
Budget Start
2012-04-01
Budget End
2013-03-31
Support Year
11
Fiscal Year
2012
Total Cost
$342,769
Indirect Cost
$126,949
Name
Stanford University
Department
Biology
Type
Schools of Medicine
DUNS #
009214214
City
Stanford
State
CA
Country
United States
Zip Code
94305
Yang, Hee Won; Collins, Sean R; Meyer, Tobias (2016) Locally excitable Cdc42 signals steer cells during chemotaxis. Nat Cell Biol 18:191-201
Hayer, Arnold; Shao, Lin; Chung, Mingyu et al. (2016) Engulfed cadherin fingers are polarized junctional structures between collectively migrating endothelial cells. Nat Cell Biol 18:1311-1323
Miyazaki, Yusuke; Mizumoto, Kota; Dey, Gautam et al. (2016) A method to rapidly create protein aggregates in living cells. Nat Commun 7:11689
Winans, Amy M; Collins, Sean R; Meyer, Tobias (2016) Waves of actin and microtubule polymerization drive microtubule-based transport and neurite growth before single axon formation. Elife 5:e12387
Ge, Xuecai; Milenkovic, Ljiljana; Suyama, Kaye et al. (2015) Phosphodiesterase 4D acts downstream of Neuropilin to control Hedgehog signal transduction and the growth of medulloblastoma. Elife 4:
Collins, Sean R; Yang, Hee Won; Bonger, Kimberly M et al. (2015) Using light to shape chemical gradients for parallel and automated analysis of chemotaxis. Mol Syst Biol 11:804
Dey, Gautam; Meyer, Tobias (2015) Phylogenetic Profiling for Probing the Modular Architecture of the Human Genome. Cell Syst 1:106-15
Dey, Gautam; Jaimovich, Ariel; Collins, Sean R et al. (2015) Systematic Discovery of Human Gene Function and Principles of Modular Organization through Phylogenetic Profiling. Cell Rep :
Galic, Milos; Tsai, Feng-Chiao; Collins, Sean R et al. (2014) Dynamic recruitment of the curvature-sensitive protein ArhGAP44 to nanoscale membrane deformations limits exploratory filopodia initiation in neurons. Elife 3:e03116
Tsai, Feng-Chiao; Seki, Akiko; Yang, Hee Won et al. (2014) A polarized Ca2+, diacylglycerol and STIM1 signalling system regulates directed cell migration. Nat Cell Biol 16:133-44

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