Modeling Biological Networks

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IV.7 CONNECTION TO SPECIFIC PROJECTS 2 (CYTOSKELETON) AND 3 (ORGANOGENESIS):

Network analysis represents a novel approach to the study of complex intracellular gene and protein networks. Instead of following the activity and function of individual proteins, we consider each as an element in an interacting cluster of many components. Project 2 (Cytoskeleton) uses the same analysis of collective behavior to consider another global intracellular network, the interconnected assembly of actin microfilaments, microtubules, and intermediate filaments. Thus Projects 1 and 2 to a large extent share methodology.

The specific connection between Projects 1 and 2 appears in the analysis of the role the cytoskeleton plays in intracellular signaling. In Project 1 Subproject 2, we investigate the correlation between cytoskeletal and signaling proteins. Even though this study depends on the topological properties of abstract protein networks, our preliminary results also reveal spatial information on the relative distribution of classes of proteins inside the cell. In particular, we find that the abstract measure we introduced for these topological maps yields a distance between proteins in which the average value is considerably smaller between cytoskeletal proteins, signaling proteins, and cytoskeletal-signaling proteins than between other proteins.

The results of our network studies will provide information on new protein interactions. This information is significant for Project 2, where such novel interactions will lead to predictions of new signaling pathways. At the same time, by ranking proteins based on their location in topological maps (e.g. whether or not they represent hubs), Project 1 will predict the relative importance of individual proteins within specific signaling pathways.

Establishing new protein interactions will also aid Project 3 (Organogenesis), which will investigate the importance of specific morphogens to development. A longstanding goal is to identify which morphogens affect this development. TGF-β is one such morphogen, but theoretical studies have revealed that at least one more morphogen with inhibitory effect on TGF-β must exist. Systematic experimental work has recently identified this inhibitor as a member of the FGF protein family. Network approaches and methods will allow us to investigate what other proteins may be relevant morphogens in avian limb organogenesis. The genetic screening experiments of Subprojects 5 to 7 will provide essential information on the genetic pathways leading to differentiation, a key component of future organogenesis simulations. The model developed in Subproject 4 will be a key component in the development of comprehensive models of the cytoskeleton and of cell differentiation which we hope eventually to integrate with our organogenesis simulations.

The network analysis will feed into the cross-scale integration of projects to produce cellular through sub-cellular simulations as discussed in sections VI and VII