? The ability to sense the direction of external chemical sources and respond by polarizing and migrating toward chemoattractants or away from chemorepellants - chemotaxis - is crucial for proper functioning of single cell organisms, such as bacteria and amoebae, as well as multi-cellular systems. Chemotaxis occurs to some extent in almost every cell type at some time during its development. While the role of chemotaxis in innate immunity has been appreciated for over a century, recent evidence suggests that this fundamental cellular response plays a major role in many aspects of development and tissue maintenance. Normal physiological processes such as lymphocyte homing, angiogenesis, embryogenesis, neurogenesis, and wound healing require accurate migration of specific cells. Inappropriate regulation of chemotaxis plays a role in excessive inflammation and inflammation-related diseases such as asthma, multiple sclerosis, and arthritis. ? ? To elucidate the mechanisms which control this dual regulation we need to appreciate how temporal responses triggered by stimulus increments relate to the spatial responses of cells in gradients. We intend to integrate mathematical analysis with quantitative measurements of the temporal and spatial changes in these enzymes to account for lipid levels in latrunculin-treated and polarized cells. To this end we plan to develop a series of mathematical and computational models and to validate them experimentally. Specifically, we propose 1) To determine the role of the complementary regulation of the 3' phosphoinositide enzymes in amplification of the external gradient; 2) To develop an interactive web-based Java applet to illustrate gradient sensing; 3) To characterize the effects on amplification of several positive feedback mechanisms. ? ?

Agency
National Institute of Health (NIH)
Institute
National Institute of General Medical Sciences (NIGMS)
Type
Research Project (R01)
Project #
1R01GM071920-01
Application #
6818866
Study Section
Special Emphasis Panel (ZRG1-BST-D (50))
Program Officer
Deatherage, James F
Project Start
2004-09-01
Project End
2008-08-31
Budget Start
2004-09-01
Budget End
2005-08-31
Support Year
1
Fiscal Year
2004
Total Cost
$413,558
Indirect Cost
Name
Johns Hopkins University
Department
Engineering (All Types)
Type
Schools of Engineering
DUNS #
001910777
City
Baltimore
State
MD
Country
United States
Zip Code
21218
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Huang, Chuan-Hsiang; Tang, Ming; Shi, Changji et al. (2013) An excitable signal integrator couples to an idling cytoskeletal oscillator to drive cell migration. Nat Cell Biol 15:1307-16
de Keijzer, S; Galloway, J; Harms, G S et al. (2011) Disrupting microtubule network immobilizes amoeboid chemotactic receptor in the plasma membrane. Biochim Biophys Acta 1808:1701-8
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Rahdar, Meghdad; Inoue, Takanari; Meyer, Tobias et al. (2009) A phosphorylation-dependent intramolecular interaction regulates the membrane association and activity of the tumor suppressor PTEN. Proc Natl Acad Sci U S A 106:480-5
Kamimura, Yoichiro; Xiong, Yuan; Iglesias, Pablo A et al. (2008) PIP3-independent activation of TorC2 and PKB at the cell's leading edge mediates chemotaxis. Curr Biol 18:1034-43
Tang, Linnan; Franca-Koh, Jonathan; Xiong, Yuan et al. (2008) tsunami, the Dictyostelium homolog of the Fused kinase, is required for polarization and chemotaxis. Genes Dev 22:2278-90
Reichl, Elizabeth M; Ren, Yixin; Morphew, Mary K et al. (2008) Interactions between myosin and actin crosslinkers control cytokinesis contractility dynamics and mechanics. Curr Biol 18:471-80

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