Numerical Tools for analyzing cell signaling circuits in normal and tumor cells The proposal, part I of a phased STTR award, describes the development of software tools, workflow and proof-of-principle case studies for detailed kinetic modeling of cell signaling pathways (and similarly complex biological processes). The most critical step in building kinetic models of real biological processes is optimizing the match between model prediction and experimental data. Achieving this optimization requires efficient means to explore alternative pathway topologies (which give rise to the structure of the model) and to """"""""calibrate"""""""" models to data (which constrains model parameters). We address both of these problems with particular emphasis on the algorithms and software needed to perform calibration of highly parametric models based on deterministic ordinary differential equations. The size of these models, the incompleteness of experimental data, and the wide range of time scales makes effective extremely calibration challenging both in theory and in practice, making the proposal innovative and significant with respect to both its biology and its applied mathematics The project is a close collaboration between a software company (Numerical) with deep expertise in chemical modeling, combustion engineering and numerical simulation and two systems biology groups (Sorger and Gunawardena) with expertise in experimental biology and computer science respectively. Three phase I specific aims include (1) Development of the Lisp-based little b programming environment as a means to represents biological pathways and multi-component protein complexes in a rapidly- revised, reusable form suitable (2) Optimizing numerical analysis tools for calibration of biological models with a sophisticated workflow and new algorithms for adjoint-based sensitivity analysis and global parameter estimation (3) Methods for validating models and applying key findings to significant problems in systems pharmacology and drug discovery.

Public Health Relevance

Numerical Tools for analyzing cell signaling circuits in normal and tumor cells The proposal, part I of a phased STTR award, describes the development of software tools, workflow and proof-of-principle case studies for detailed kinetic modeling of cell signaling pathways (and similarly complex biological processes). Achieving this requires efficient means to explore alternative pathway topologies (which give rise to the structure of the model) and to calibrate models to data (which constrains model parameters). We address both of these problems with particular emphasis on the algorithms and software needed to perform calibration of highly parametric models based on deterministic ordinary differential equations. The size of these models, the incompleteness of experimental data, and the wide range of time scales makes effective extremely calibration challenging both in theory and in practice, making the proposal innovative and significant with respect to both its biology and its applied mathematics

Agency
National Institute of Health (NIH)
Institute
National Institute of Biomedical Imaging and Bioengineering (NIBIB)
Type
Small Business Technology Transfer (STTR) Grants - Phase I (R41)
Project #
1R41EB008414-01A1
Application #
7670716
Study Section
Special Emphasis Panel (ZRG1-BST-F (10))
Program Officer
Peng, Grace
Project Start
2009-08-01
Project End
2011-07-31
Budget Start
2009-08-01
Budget End
2010-07-31
Support Year
1
Fiscal Year
2009
Total Cost
$150,000
Indirect Cost
Name
Numerica Technology, Inc.
Department
Type
DUNS #
157645537
City
Cambridge
State
MA
Country
United States
Zip Code
02142