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.
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.
|Almaden, Jonathan V; Liu, Yi C; Yang, Edward et al. (2016) B-cell survival and development controlled by the coordination of NF-?B family members RelB and cRel. Blood 127:1276-86|
|Ourthiague, Diana R; Birnbaum, Harry; Ortenlöf, Niklas et al. (2015) Limited specificity of IRF3 and ISGF3 in the transcriptional innate-immune response to double-stranded RNA. J Leukoc Biol 98:119-28|
|Shokhirev, Maxim N; Almaden, Jonathan; Davis-Turak, Jeremy et al. (2015) A multi-scale approach reveals that NF-?B cRel enforces a B-cell decision to divide. Mol Syst Biol 11:783|
|Suryawanshi, Gajendra W; Hoffmann, Alexander (2015) A multi-scale mathematical modeling framework to investigate anti-viral therapeutic opportunities in targeting HIV-1 accessory proteins. J Theor Biol 386:89-104|
|Tsui, Rachel; Kearns, Jeffrey D; Lynch, Candace et al. (2015) I?B? enhances the generation of the low-affinity NF?B/RelA homodimer. Nat Commun 6:7068|
|Almaden, Jonathan V; Tsui, Rachel; Liu, Yi C et al. (2014) A pathway switch directs BAFF signaling to distinct NF?B transcription factors in maturing and proliferating B cells. Cell Rep 9:2098-111|
|Alves, Bryce N; Tsui, Rachel; Almaden, Jonathan et al. (2014) I?B? is a key regulator of B cell expansion by providing negative feedback on cRel and RelA in a stimulus-specific manner. J Immunol 192:3121-32|
|Shih, Vincent F-S; Davis-Turak, Jeremy; Macal, Monica et al. (2012) Control of RelB during dendritic cell activation integrates canonical and noncanonical NF-?B pathways. Nat Immunol 13:1162-70|
|Schröfelbauer, Bärbel; Polley, Smarajit; Behar, Marcelo et al. (2012) NEMO ensures signaling specificity of the pleiotropic IKK? by directing its kinase activity toward I?B?. Mol Cell 47:111-21|
|Basak, Soumen; Behar, Marcelo; Hoffmann, Alexander (2012) Lessons from mathematically modeling the NF-*B pathway. Immunol Rev 246:221-38|
Showing the most recent 10 out of 15 publications