The B-cell compartment undergoes dramatic expansion during immune responses. This is achieved by the combined control of one of the most rapid proliferation rates known for mammalian cells, and the regulation of B-cell survival and death. Misregulation of these processes causes a variety of B-cell lymphomas. The NFkB signaling system plays a critical role in B-cell activation, as evidenced by B- cell activation phenotypes in knockout mice deficient in NFkB proteins. Two distinct NFkB activation pathways have been described to induce overlapping sets of NF-kB transcription factors containing the three activation-domain-containing NFkB proteins, RelA, RelB, and cRel. However, recent work in other cell types indicates that the generation and activation of these NFkB dimers involves a number of interdependent mechanisms, and that the NFkB signaling system integrates distinct cellular stimuli. Mathematical modeling of the NFkB signaling system has proven useful as a predictive tool to explore signaling crosstalk between distinct stimuli. Here, we propose to construct an experimentally validated mathematical model of the NFkB signaling system in B-cells to investigate its capacity to integrate pro-survival and pro-proliferative (mitogenic) stimuli. Further, we will employ a previously constructed mathematical modeling at the cellular scale (CYTON) to interpret quantitative experimental analysis of NFkB knockouts to delineate the functions of the major NFkB dimers in B-cell survival and proliferation (cell division) in response to B-cell activating signals. We propose to link the biochemical and cell biological scale models to investigate the synergistic effects of exposure to multiple stimuli in B-cell activation. Indeed, the combined mathematical model enables the first modeling-directed experimental studies of signaling protein functions in the activation program of any immune cell. We will apply this tool to probe the molecular mechanisms underlying the variance in cell fate decisions, synergistic effects of co-stimulation scenarios, and misregulated stimulus-responsive B-cell expansion characteristics in mouse strains with defined genetic alterations and human chronic lymphocytic leukemia (CLL) patient samples.

Public Health Relevance

B-cell activation plays critical roles in adaptive immune responses and immunological memory, but misregulation is a major cause of immune cell cancers. The NFkB Signaling System produces several different dimeric transcription factors and regulates their activity on response to inflammatory and immune activation stimuli. The proposed studies involve quantitative measurements and mathematical modeling at the molecular and cellular scales to understand the regulation of NFkB dimers during B-cell activation and determine how they regulate expansion in response to activating stimuli of normal, healthy B-cells, as well as tumorigenic B-cells derived from human cancer patients.

Agency
National Institute of Health (NIH)
Institute
National Institute of Allergy and Infectious Diseases (NIAID)
Type
Research Project (R01)
Project #
5R01AI083453-05
Application #
8582530
Study Section
Cellular and Molecular Immunology - A Study Section (CMIA)
Program Officer
Mallia, Conrad M
Project Start
2009-12-15
Project End
2014-11-30
Budget Start
2013-12-01
Budget End
2014-11-30
Support Year
5
Fiscal Year
2014
Total Cost
$307,404
Indirect Cost
$97,467
Name
University of California San Diego
Department
Chemistry
Type
Schools of Arts and Sciences
DUNS #
804355790
City
La Jolla
State
CA
Country
United States
Zip Code
92093
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Wuerzberger-Davis, Shelly M; Chen, Yuhong; Yang, David T et al. (2011) Nuclear export of the NF-?B inhibitor I?B? is required for proper B cell and secondary lymphoid tissue formation. Immunity 34:188-200
Cheng, Christine S; Feldman, Kristyn E; Lee, James et al. (2011) The specificity of innate immune responses is enforced by repression of interferon response elements by NF-ýýB p50. Sci Signal 4:ra11