The overall goal of this project is to understand how the shape of cells in the context of tissue organization controls transmembrane signal transduction. In the previous term we had found that cells with different aspect ratios produce transient microdomains of activated receptors and differentially regulate cytoplasmic and nuclear signaling. Building on these observations in the coming term we plan to use a combination of constrained analytic representations and numerical simulations with super resolution imaging of biochemical reactions in individual cells assembled within engineered 3D chips to mimic tissue organization to obtain deep understanding of transmembrane signaling when the cell is part of the 3D tissue environment. Our central hypothesis is that within tissues, cells, to maintain their functional phenotype sense a multifaceted relationship between extra and intra cellular spaces and density of receptors at the cell surface, in the context of various cell shapes. This multidimensional relationship controls transmembrane signal transduction and cell health. To test our central hypothesis we propose to develop analytical models of role of cell shape in information storage and retrieval as cells function within tissues. We will address one key question: 1) how changes in intra and extracellular spaces and consequently their effect on concentrations of soluble components such as receptor agonists, and intracellular adapters and transducers separated by the plasma membrane and membrane bound receptors interact to regulate transmembrane signaling. Using human and rat vascular smooth muscle cells as model systems we will use the analytical representations to develop multicompartment ODE and PDE models and run numerical simulations to determine how relationships between intracellular and extracellular spaces and cell shape control transmembrane signal transduction. To test model predictions we will develop 3D chips ? microfabricated devices that enable the assembly of multilayered cells of different shapes and varying extracellular spaces to mimic organization of these cells within tissues. .We will then test model predictions of control of formation of activated receptor signaling complexes using super resolution fluorescence microscopy and single molecule fluorescence spectroscopy. From these studies we hope to elucidate fundamental principles of how cell shape and tissue organization information is processed at the transmembrane level.

Public Health Relevance

The shape of cells within tissues is an indicator of health and disease. However we understand little of the physico?chemical principles of how cell shape relates to disease. In this project we will use mathematical modeling and experiments to understand cellular communication and its role in cell health in the tissue environment.

Agency
National Institute of Health (NIH)
Institute
National Institute of General Medical Sciences (NIGMS)
Type
Research Project (R01)
Project #
5R01GM072853-10
Application #
9199087
Study Section
Special Emphasis Panel (ZRG1)
Program Officer
Dunsmore, Sarah
Project Start
2005-03-01
Project End
2019-12-31
Budget Start
2017-01-01
Budget End
2017-12-31
Support Year
10
Fiscal Year
2017
Total Cost
Indirect Cost
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
Ron, Amit; Azeloglu, Evren U; Calizo, Rhodora C et al. (2017) Cell shape information is transduced through tension-independent mechanisms. Nat Commun 8:2145
Scarlata, Suzanne; Singla, Ashima; Garwain, Osama (2017) Phospholipase C? interacts with cytosolic partners to regulate cell proliferation. Adv Biol Regul :
Hu, Mufeng; Azeloglu, Evren U; Ron, Amit et al. (2017) A biomimetic gelatin-based platform elicits a pro-differentiation effect on podocytes through mechanotransduction. Sci Rep 7:43934
Guo, Yuanjian; Yang, Lu; Haught, Katrina et al. (2015) Osmotic Stress Reduces Ca2+ Signals through Deformation of Caveolae. J Biol Chem 290:16698-707
Guo, Yuanjian; Lu, Zhongju; Cohen, Ira Stephen et al. (2015) Development of a universal RNA beacon for exogenous gene detection. Stem Cells Transl Med 4:476-82
Sahu, Shriya; Philip, Finly; Scarlata, Suzanne (2014) Hydrolysis rates of different small interfering RNAs (siRNAs) by the RNA silencing promoter complex, C3PO, determines their regulation by phospholipase C?. J Biol Chem 289:5134-44
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

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