For over a hundred years it has been empirically known that shape of cells within tissues and organs is an indicator of health or disease. The field of pathology is largely based on the premise the cell shape contributes to tissue morphology which can serve as a diagnostic of disease initiation and progression. Nevertheless, the biological basis for these empirical observations has never been tackled in a systematic manner. We have been studying how cell shape affects information flow through cell signaling networks. We use a combination of mathematical analyses, numerical simulations and live cell imaging to understand the role of cell shape in signal transduction. Our overall hypothesis is that cell shape can regulate dynamic membrane localization of upstream signaling components such as receptors and this localization coupled with network topology and scaffolding of select isoforms of negative regulators in the cytoplasm are major determinants of the spatial specificity of signaling. To test this hypothesis we will 1) study the role the of cell shape in the dynamics in the plane of the membrane of receptors that regulate the cAMP and MAP-kinase pathways 2) study the relationship between cell shape and different isoforms of cAMP phosphodiesterases in regulating receptor- stimulated cAMP levels and activated MAPK-1,2 within microdomains 3) study the role of how regulated scaffolding of the different isoforms of the negative regulators cAMP phosphodiesterases and phosphatases controls receptor triggered cAMP and MAPK 1,2 microdomains in cells of differing shapes. Since many diseases arise from malfunction of cell signaling pathways, understanding the role of cell shape in control of intracellular signaling will shed light on the origins of cancer, heart failure and kidney disease. These studies will provide new knowledge that will contribute to the process of putting image based diagnosis on firm biological principles. Thus, we anticipate the potential significance of the project will lie in its contributions to both the basic field of systems biology and the medical discipline of pathology.

Public Health Relevance

This project is focused on understanding how the shape of cells affects communication within the cells. We propose to use a combination of computer based models and experiments. These studies will shed light on how changes in cell shape that often accompany disease processes affect the functioning of cells.

Agency
National Institute of Health (NIH)
Institute
National Institute of General Medical Sciences (NIGMS)
Type
Research Project (R01)
Project #
5R01GM072853-06
Application #
8213535
Study Section
Special Emphasis Panel (ZRG1-CB-J (03))
Program Officer
Lyster, Peter
Project Start
2005-03-01
Project End
2014-12-31
Budget Start
2012-01-01
Budget End
2012-12-31
Support Year
6
Fiscal Year
2012
Total Cost
$546,139
Indirect Cost
$163,337
Name
Icahn School of Medicine at Mount Sinai
Department
Pharmacology
Type
Schools of Medicine
DUNS #
078861598
City
New York
State
NY
Country
United States
Zip Code
10029
Rangamani, Padmini; Xiong, Granville Yuguang; Iyengar, Ravi (2014) Multiscale modeling of cell shape from the actin cytoskeleton. Prog Mol Biol Transl Sci 123:143-67
Rangamani, Padmini; Lipshtat, Azi; Azeloglu, Evren U et al. (2013) Decoding information in cell shape. Cell 154:1356-69
Rangamani, Padmini; Fardin, Marc-Antoine; Xiong, Yuguang et al. (2011) Signaling network triggers and membrane physical properties control the actin cytoskeleton-driven isotropic phase of cell spreading. Biophys J 100:845-57
Xiong, Yuguang; Rangamani, Padmini; Fardin, Marc-Antoine et al. (2010) Mechanisms controlling cell size and shape during isotropic cell spreading. Biophys J 98:2136-46
Neves, Susana R; Iyengar, Ravi (2009) Models of spatially restricted biochemical reaction systems. J Biol Chem 284:5445-9
Lipshtat, Azi; Neves, Susana R; Iyengar, Ravi (2009) Specification of spatial relationships in directed graphs of cell signaling networks. Ann N Y Acad Sci 1158:44-56
Bromberg, Kenneth D; Ma'ayan, Avi; Neves, Susana R et al. (2008) Design logic of a cannabinoid receptor signaling network that triggers neurite outgrowth. Science 320:903-9
Lipshtat, Azi; Purushothaman, Sudarshan P; Iyengar, Ravi et al. (2008) Functions of bifans in context of multiple regulatory motifs in signaling networks. Biophys J 94:2566-79
Neves, Susana R; Tsokas, Panayiotis; Sarkar, Anamika et al. (2008) Cell shape and negative links in regulatory motifs together control spatial information flow in signaling networks. Cell 133:666-80
Berger, Seth I; Iyengar, Ravi; Ma'ayan, Avi (2007) AVIS: AJAX viewer of interactive signaling networks. Bioinformatics 23:2803-5

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