Construction of a Computable Network Model for DNA Damage, Autophagy, Cell Death, and Senescence

Abstract

Towards the development of a systems biology-based risk assessment approach for environmental toxicants, including tobacco products in a systems toxicology setting such as the “21st Century Toxicology”, we are building a series of computable biological network models specific to non-diseased pulmonary and cardiovascular cells/tissues which capture the molecular events that can be activated following exposure to environmental toxicants. Here we extend on previous work and report on the construction and evaluation of a mechanistic network model focused on DNA damage response and the four main cellular fates induced by stress: autophagy, apoptosis, necroptosis, and senescence. In total, the network consists of 34 sub-models containing 1052 unique nodes and 1538 unique edges which are supported by 1231 PubMed-referenced literature citations. Causal node-edge relationships are described using the Biological Expression Language (BEL), which allows for the semantic representation of life science relationships in a computable format. The Network is provided in .XGMML format and can be viewed using freely available network visualization software, such as Cytoscape.

Causal Biological Network Database: A Comprehensive Platform of Causal Biological Network Models Focused on the Pulmonary and Vascular Systems

“…The first versions of 98 network models (Version 1.0) were constructed and evaluated following the strategy reported previously (7)(8)(9)(10)(11)(12). This strategy ( Figure 3A and B) is summarized briefly here:…”

“…Structurally, the CBN collection is organized into the following biological areas (Figure 1): cell response to stress, cell proliferation, cell fate (including DNA damage response, autophagy, senescence, apoptosis and necroptosis), tissue repair and angiogenesis, pulmonary inflammatory processes, vascular inflammatory processes and chronic obstructive pulmonary disease (COPD)-specific networks. Details of these network models have been published previously (7)(8)(9)(10)(11)(12).…”

Enhancement of COPD biological networks using a web-based collaboration interface

“…These networks cover mechanisms of cell proliferation 5 , cell stress 4 , DNA damage, autophagy, cell death and senescence 3 , pulmonary inflammation 6 , and tissue repair and angiogenesis 7 in the non-diseased pulmonary context. To create COPD-relevant networks, these non-diseased networks were enhanced by incorporating COPD mechanisms sourced using a literature and data set approach ( Figure 1) in an iterative approach, as described in detail for the non-diseased network model construction, by a team of subject matter experts in computational biology, molecular biology, inhalation toxicology, and COPD.…”

“…The 90 previously published non-diseased network models used for the initial substrate included networks involved in cell proliferation 5 , cell stress 4 , DNA damage, apoptosis, senescence, autophagy, necroptosis (DACS) 3 , pulmonary inflammation (IPN) 6 , and tissue repair and angiogenesis (TRAG) 7 . The Endothelial Shear Stress network from the cell stress model was excluded because the focus of the COPD Network was to describe lung biology.…”

Developing Network-Based Systems Toxicology by Combining Transcriptomics Data with Literature Mining and Multiscale Quantitative Modeling

“…The initial mechanistic interest focused on the lung biology, and version 1.0 of the collection consisted of 108 assembled causal networks regrouped into five high-level functional families (cell proliferation 15 [53], cellular stress 7 [54], cell fate 34 [55], pulmonary inflammation 24 [56], and tissue repair/angiogenesis 9 [57]). The design and assembly processes were the same for all the networks, each of them having been defined by biological boundaries chosen to globally cover all of the essential biological processes and responses of healthy lung tissues (Figure 3).…”