Combining Computational and Experimentation to Interrogate NF-kappaB Signaling

描述（由申请人提供）：本研究的目的是使用系统生物学方法来了解控制转录因子NF-kappaB激活的特异性和时间机制，以及NF-kappaB如何引发转录反应，以便更好地了解某些类型癌症的进展。基于系统的方法和计算方法特别适合解决这个问题。

DESCRIPTION (provided by applicant): The purpose of this research is to use systems biology approaches to understand the specificity and temporal mechanisms that govern activation of transcription factor NF-kappaB, as well as how NF-kappaB evokes a transcriptional response, in order to better understand progression of certain types of cancer. Systems-based and computational approaches are particularly well-suited to address this issue. Using a combined computational modeling/experimental approach, we were able to characterize a previously-unknown part of the pathways which led from LPS stimulation to NF-kappaB activation. This approach also led to the explanation of a complex behavior: the observed stable activation of NF-kappaB under LPS stimulation. Moving forward, we propose to continue using an integrated approach to study the NF-kappaB network at several levels of abstraction. Our Specific Aims are to: (1) reconstruct and analyze a network model of the entire known NF-kappaB signaling and transcriptional network; (2) derive a detailed description and model of the gene expression response to NF-kappaB activation; (3) build a quantitative description of B cell-related NF-kappaB activation dynamics into a detailed computational model; and (4) observe and model NF-kappaB-related activation and autocrine/paracrine signaling in single cells. PLAIN LANGUAGE SUMMARY: Advances in our ability to build computer models, and to use model predictions to guide experiments, have great potential in helping us to understand cancer progression. We propose to use computer modeling and experiments to help us understand the NF-kappaB signaling network and its role in cancer development, particularly with regard to diffuse large B cell lymphomas.