The overall, long term goal of this work is to develop ways to manipulate cellular responses initiated by ligand/receptor binding; this is done through the combination of mathematical modeling and experiment. The proposed work focuses on developing mathematical models for guanine nucleotide binding protein (G-protein) coupled receptors and G-protein activation. G-proteins are found in virtually every tissue, and they play key roles in, for example, the immune system, vision, brain function, and heart regulation. The activation of G-proteins by receptors at the cell surface initiates a signal transduction pathway that is complex and poorly understood. Receptors can exist in multiple states (active, inactive, ligand-bound, desensitized, internalized, etc.) and these states influence G-protein activation. Further, the kinetics of the transitions between receptor states appear to be important in determining levels and dynamics of G-protein activation and thus a variety of cellular responses. Despite the obvious complexity and dynamics of these signaling processes, most work in the field concentrates on relatively simple equilibrium models of the system. More accurate models of G-protein coupled receptors and G-protein activation are essential to understanding how effective bound ligands are at eliciting cellular responses. Such information is critical to the rational manipulation of cell function for purposes of cell and tissue engineering, and for the development of methods for the development and/or discovery of new phamaceuticals. In this proposal, kinetic models of the G-protein coupled receptor signaling pathway will be developed. Specifically, we will use these models to (1) test the hypothesis that ligand efficacy may be dramatically manipulated by altering cellular parameters, (2) demonstrate the influence that ligand-specific parameters have on signaling and desensitization, and (3) demonstrate conditions under which receptor dimerization may cause larger scale clustering and thus influence signaling. Finally, (4) we will test the hypothesis that common high throughput drug screening assays may be biased against the detection of a class of ligands known as inverse agonists. In each case, models will be used to make predictions that are experimentally accessible and have application to a wide range of G-protein coupled receptor systems.

Agency
National Institute of Health (NIH)
Institute
National Institute of General Medical Sciences (NIGMS)
Type
Research Project (R01)
Project #
5R01GM062930-03
Application #
6636617
Study Section
Pharmacology A Study Section (PHRA)
Program Officer
Lograsso, Philip
Project Start
2001-04-01
Project End
2005-03-31
Budget Start
2003-04-01
Budget End
2005-03-31
Support Year
3
Fiscal Year
2003
Total Cost
$165,442
Indirect Cost
Name
University of Michigan Ann Arbor
Department
Engineering (All Types)
Type
Schools of Engineering
DUNS #
073133571
City
Ann Arbor
State
MI
Country
United States
Zip Code
48109
Zhao, Shuang; Chang, S Laura; Linderman, Jennifer J et al. (2014) A Comprehensive Analysis of CXCL12 Isoforms in Breast Cancer(1,2.) Transl Oncol :
Fallahi-Sichani, Mohammad; Linderman, Jennifer J (2009) Lipid raft-mediated regulation of G-protein coupled receptor signaling by ligands which influence receptor dimerization: a computational study. PLoS One 4:e6604
Linderman, Jennifer J (2009) Modeling of G-protein-coupled receptor signaling pathways. J Biol Chem 284:5427-31
Brinkerhoff, Christopher J; Choi, Ji Sun; Linderman, Jennifer J (2008) Diffusion-limited reactions in G-protein activation: unexpected consequences of antagonist and agonist competition. J Theor Biol 251:561-9
Brinkerhoff, Christopher J; Traynor, John R; Linderman, Jennifer J (2008) Collision coupling, crosstalk, and compartmentalization in G-protein coupled receptor systems: can a single model explain disparate results? J Theor Biol 255:278-86
Kinzer-Ursem, Tamara L; Linderman, Jennifer J (2007) Both ligand- and cell-specific parameters control ligand agonism in a kinetic model of g protein-coupled receptor signaling. PLoS Comput Biol 3:e6
Kinzer-Ursem, Tamara L; Sutton, Karyn L; Waller, Anna et al. (2006) Multiple receptor states are required to describe both kinetic binding and activation of neutrophils via N-formyl peptide receptor ligands. Cell Signal 18:1732-47
Brinkerhoff, Christopher J; Linderman, Jennifer J (2005) Integrin dimerization and ligand organization: key components in integrin clustering for cell adhesion. Tissue Eng 11:865-76
Waller, Anna; Sutton, Karyn L; Kinzer-Ursem, Tamara L et al. (2004) Receptor binding kinetics and cellular responses of six N-formyl peptide agonists in human neutrophils. Biochemistry 43:8204-16
Brinkerhoff, Christopher J; Woolf, Peter J; Linderman, Jennifer J (2004) Monte Carlo simulations of receptor dynamics: insights into cell signaling. J Mol Histol 35:667-77

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