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Molecular Architecture of Spinal Cord Injury Protein Interaction Network.

Alawieh A, Sabra M, Sabra Z, Tomlinson S, Zaraket FA - PLoS ONE (2015)

Bottom Line: Pathway analysis of the interactome and the rich-club revealed high similarity indicating the role of the rich-club proteins as hubs of the most prominent pathways in disease pathophysiology and illustrating the centrality of pro-and anti-survival signal competition in the pathology of SCI.In addition, evaluation of centrality measures of single nodes within the rich-club have revealed that neuronal growth factor (NGF), caspase 3, and H-Ras are the most central nodes and potentially an interesting targets for therapy.Our integrative approach uncovers the molecular architecture of SCI interactome, and provide an essential resource for evaluating significant therapeutic candidates.

View Article: PubMed Central - PubMed

Affiliation: Neuroscience Institute, Department of Neurosciences, Medical University of South Carolina, Charleston, SC 29425, United States of America; Department of Electrical and Computer Engineering, American University of Beirut, Beirut, Lebanon.

ABSTRACT
Spinal cord injury (SCI) is associated with complex pathophysiological processes that follow the primary traumatic event and determine the extent of secondary damage and functional recovery. Numerous reports have used global and hypothesis-driven approaches to identify protein changes that contribute to the overall pathology of SCI in an effort to identify potential therapeutic interventions. In this study, we use a semi-automatic annotation approach to detect terms referring to genes or proteins dysregulated in the SCI literature and develop a curated SCI interactome. Network analysis of the SCI interactome revealed the presence of a rich-club organization corresponding to a "powerhouse" of highly interacting hub-proteins. Studying the modular organization of the network have shown that rich-club proteins cluster into modules that are specifically enriched for biological processes that fall under the categories of cell death, inflammation, injury recognition and systems development. Pathway analysis of the interactome and the rich-club revealed high similarity indicating the role of the rich-club proteins as hubs of the most prominent pathways in disease pathophysiology and illustrating the centrality of pro-and anti-survival signal competition in the pathology of SCI. In addition, evaluation of centrality measures of single nodes within the rich-club have revealed that neuronal growth factor (NGF), caspase 3, and H-Ras are the most central nodes and potentially an interesting targets for therapy. Our integrative approach uncovers the molecular architecture of SCI interactome, and provide an essential resource for evaluating significant therapeutic candidates.

No MeSH data available.


Related in: MedlinePlus

Network properties of the SCI interactome.(A) Power-Law distribution of nodes in the SCII showing a pattern typical of a scale free network: High frequency of non-hub nodes (nodes with few connections) and low frequency of hubs (nodes with high connections). (B) Detection of rich-club organization in the SCII. As described in methods, rich-club coefficient (φ(k)) was computed across the range of degrees in the network and compared to the rich-club coefficient (φ¬random(k)) of 1000 comparable random networks. Raw rich-club coefficient measures mapped to right vertical axis. Normalized coefficient mapped to the left vertical axis. A normalized coefficient > 1 indicates an RC organization. One sample t-test, ****average p-value = 2 E-12. (D) Frequency in literature of rich-club vs. non-rich-club proteins. Mean +/- SEM. Student t-test. *** p<0.0001.
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pone.0135024.g003: Network properties of the SCI interactome.(A) Power-Law distribution of nodes in the SCII showing a pattern typical of a scale free network: High frequency of non-hub nodes (nodes with few connections) and low frequency of hubs (nodes with high connections). (B) Detection of rich-club organization in the SCII. As described in methods, rich-club coefficient (φ(k)) was computed across the range of degrees in the network and compared to the rich-club coefficient (φ¬random(k)) of 1000 comparable random networks. Raw rich-club coefficient measures mapped to right vertical axis. Normalized coefficient mapped to the left vertical axis. A normalized coefficient > 1 indicates an RC organization. One sample t-test, ****average p-value = 2 E-12. (D) Frequency in literature of rich-club vs. non-rich-club proteins. Mean +/- SEM. Student t-test. *** p<0.0001.

Mentions: Similar to other biological networks, we found that the SCI interactome exhibited both scale-free and small-word properties. Degree distribution of SCII nodes show a power-law distribution consisting a high frequency of proteins with low connections, and very few genes with high connections, i.e. hubs [21] (Fig 3a). General features of the network are also compatible with small-world organization with a relatively low path length (s = 2.45) and high clustering coefficient (t = 0.42), yielding a significantly higher small-world coefficient compared to random networks [22] (Fig 3b). Since scale-free networks can exhibit special topological orders, such as knotty centres (a connective core within the network [17]) or a rich-club (a dense core of highly interconnected nodes [16]), we assayed for the presence of such organizations in the SCII. A principal finding of this paper is the identification and characterization of a rich-club organization in the SCII. (Fig 3c) shows the normalized rich-club coefficient (ρ(k)) of the SCII network over the range of node-specific degrees (k) along with the raw rich-club coefficient (φ(k)) and random rich club coefficient (φrandom(k)), derived from 1000 randomly generated networks. The shaded region indicates the region of the rich-club covering the p(k) range 36–203. For statistical confirmation, a one-sample t-test was carried out over the range of the rich-club; comparing network coefficients to that of random networks revealed a high significance (average p-value across rich-club range = 2xE-12). In the context of disease related protein interactome, the characterization of the rich-club provides avenues for the exploration of pathways and proteins that form the powerhouse of the overall network of pathophysiology.


Molecular Architecture of Spinal Cord Injury Protein Interaction Network.

Alawieh A, Sabra M, Sabra Z, Tomlinson S, Zaraket FA - PLoS ONE (2015)

Network properties of the SCI interactome.(A) Power-Law distribution of nodes in the SCII showing a pattern typical of a scale free network: High frequency of non-hub nodes (nodes with few connections) and low frequency of hubs (nodes with high connections). (B) Detection of rich-club organization in the SCII. As described in methods, rich-club coefficient (φ(k)) was computed across the range of degrees in the network and compared to the rich-club coefficient (φ¬random(k)) of 1000 comparable random networks. Raw rich-club coefficient measures mapped to right vertical axis. Normalized coefficient mapped to the left vertical axis. A normalized coefficient > 1 indicates an RC organization. One sample t-test, ****average p-value = 2 E-12. (D) Frequency in literature of rich-club vs. non-rich-club proteins. Mean +/- SEM. Student t-test. *** p<0.0001.
© Copyright Policy
Related In: Results  -  Collection

License
Show All Figures
getmorefigures.php?uid=PMC4524728&req=5

pone.0135024.g003: Network properties of the SCI interactome.(A) Power-Law distribution of nodes in the SCII showing a pattern typical of a scale free network: High frequency of non-hub nodes (nodes with few connections) and low frequency of hubs (nodes with high connections). (B) Detection of rich-club organization in the SCII. As described in methods, rich-club coefficient (φ(k)) was computed across the range of degrees in the network and compared to the rich-club coefficient (φ¬random(k)) of 1000 comparable random networks. Raw rich-club coefficient measures mapped to right vertical axis. Normalized coefficient mapped to the left vertical axis. A normalized coefficient > 1 indicates an RC organization. One sample t-test, ****average p-value = 2 E-12. (D) Frequency in literature of rich-club vs. non-rich-club proteins. Mean +/- SEM. Student t-test. *** p<0.0001.
Mentions: Similar to other biological networks, we found that the SCI interactome exhibited both scale-free and small-word properties. Degree distribution of SCII nodes show a power-law distribution consisting a high frequency of proteins with low connections, and very few genes with high connections, i.e. hubs [21] (Fig 3a). General features of the network are also compatible with small-world organization with a relatively low path length (s = 2.45) and high clustering coefficient (t = 0.42), yielding a significantly higher small-world coefficient compared to random networks [22] (Fig 3b). Since scale-free networks can exhibit special topological orders, such as knotty centres (a connective core within the network [17]) or a rich-club (a dense core of highly interconnected nodes [16]), we assayed for the presence of such organizations in the SCII. A principal finding of this paper is the identification and characterization of a rich-club organization in the SCII. (Fig 3c) shows the normalized rich-club coefficient (ρ(k)) of the SCII network over the range of node-specific degrees (k) along with the raw rich-club coefficient (φ(k)) and random rich club coefficient (φrandom(k)), derived from 1000 randomly generated networks. The shaded region indicates the region of the rich-club covering the p(k) range 36–203. For statistical confirmation, a one-sample t-test was carried out over the range of the rich-club; comparing network coefficients to that of random networks revealed a high significance (average p-value across rich-club range = 2xE-12). In the context of disease related protein interactome, the characterization of the rich-club provides avenues for the exploration of pathways and proteins that form the powerhouse of the overall network of pathophysiology.

Bottom Line: Pathway analysis of the interactome and the rich-club revealed high similarity indicating the role of the rich-club proteins as hubs of the most prominent pathways in disease pathophysiology and illustrating the centrality of pro-and anti-survival signal competition in the pathology of SCI.In addition, evaluation of centrality measures of single nodes within the rich-club have revealed that neuronal growth factor (NGF), caspase 3, and H-Ras are the most central nodes and potentially an interesting targets for therapy.Our integrative approach uncovers the molecular architecture of SCI interactome, and provide an essential resource for evaluating significant therapeutic candidates.

View Article: PubMed Central - PubMed

Affiliation: Neuroscience Institute, Department of Neurosciences, Medical University of South Carolina, Charleston, SC 29425, United States of America; Department of Electrical and Computer Engineering, American University of Beirut, Beirut, Lebanon.

ABSTRACT
Spinal cord injury (SCI) is associated with complex pathophysiological processes that follow the primary traumatic event and determine the extent of secondary damage and functional recovery. Numerous reports have used global and hypothesis-driven approaches to identify protein changes that contribute to the overall pathology of SCI in an effort to identify potential therapeutic interventions. In this study, we use a semi-automatic annotation approach to detect terms referring to genes or proteins dysregulated in the SCI literature and develop a curated SCI interactome. Network analysis of the SCI interactome revealed the presence of a rich-club organization corresponding to a "powerhouse" of highly interacting hub-proteins. Studying the modular organization of the network have shown that rich-club proteins cluster into modules that are specifically enriched for biological processes that fall under the categories of cell death, inflammation, injury recognition and systems development. Pathway analysis of the interactome and the rich-club revealed high similarity indicating the role of the rich-club proteins as hubs of the most prominent pathways in disease pathophysiology and illustrating the centrality of pro-and anti-survival signal competition in the pathology of SCI. In addition, evaluation of centrality measures of single nodes within the rich-club have revealed that neuronal growth factor (NGF), caspase 3, and H-Ras are the most central nodes and potentially an interesting targets for therapy. Our integrative approach uncovers the molecular architecture of SCI interactome, and provide an essential resource for evaluating significant therapeutic candidates.

No MeSH data available.


Related in: MedlinePlus