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A Rich-Club Organization in Brain Ischemia Protein Interaction Network.

Alawieh A, Sabra Z, Sabra M, Tomlinson S, Zaraket FA - Sci Rep (2015)

Bottom Line: Functional annotation of the interactome uncovered prominent pathways and highlighted the critical role of the complement and coagulation cascade in the initiation and amplification of injury starting by activation of the rich-club.We performed an in-silico screen for putative interventions that have pleiotropic effects on rich-club components and we identified estrogen as a prominent candidate.Our findings show that complex network analysis of disease related interactomes may lead to a better understanding of pathogenic mechanisms and provide cost-effective and mechanism-based discovery of candidate therapeutics.

View Article: PubMed Central - PubMed

Affiliation: Department of Neurosciences, Medical University of South Carolina, Charleston, SC 29425.

ABSTRACT
Ischemic stroke involves multiple pathophysiological mechanisms with complex interactions. Efforts to decipher those mechanisms and understand the evolution of cerebral injury is key for developing successful interventions. In an innovative approach, we use literature mining, natural language processing and systems biology tools to construct, annotate and curate a brain ischemia interactome. The curated interactome includes proteins that are deregulated after cerebral ischemia in human and experimental stroke. Network analysis of the interactome revealed a rich-club organization indicating the presence of a densely interconnected hub structure of prominent contributors to disease pathogenesis. Functional annotation of the interactome uncovered prominent pathways and highlighted the critical role of the complement and coagulation cascade in the initiation and amplification of injury starting by activation of the rich-club. We performed an in-silico screen for putative interventions that have pleiotropic effects on rich-club components and we identified estrogen as a prominent candidate. Our findings show that complex network analysis of disease related interactomes may lead to a better understanding of pathogenic mechanisms and provide cost-effective and mechanism-based discovery of candidate therapeutics.

No MeSH data available.


Related in: MedlinePlus

Venn Diagram of the distribution of BII proteins on different significantly enriched KEGG pathways.(A) Pathways with p-value less than 10^–12 are included. Complement and coagulation cascade (CCC) is the most enriched pathway and together with calcium signaling and MAPK signaling pathways form the three most significant pathways in our BII. Notably, Complement and Coagulation Pathway has little overlap in terms of components (4.4%) with other pathways compared to the latter two major pathways (22% and 48%). (B) Protein -protein interactions among the three most prominent pathways in the network. White dots indicate a node (protein) and edges indicate interactions. Red edges denote interactions that involve the CCC. Other edges are colored green. Despite the minimal intersection in terms of components between the CCC and other pathways, this cascade is still heavily interconnected with other prominent pathways in the network.
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f2: Venn Diagram of the distribution of BII proteins on different significantly enriched KEGG pathways.(A) Pathways with p-value less than 10^–12 are included. Complement and coagulation cascade (CCC) is the most enriched pathway and together with calcium signaling and MAPK signaling pathways form the three most significant pathways in our BII. Notably, Complement and Coagulation Pathway has little overlap in terms of components (4.4%) with other pathways compared to the latter two major pathways (22% and 48%). (B) Protein -protein interactions among the three most prominent pathways in the network. White dots indicate a node (protein) and edges indicate interactions. Red edges denote interactions that involve the CCC. Other edges are colored green. Despite the minimal intersection in terms of components between the CCC and other pathways, this cascade is still heavily interconnected with other prominent pathways in the network.

Mentions: KEGG (Kyoto Encyclopedia of Genes and Genomes)14 pathway annotation revealed that complement and coagulation cascade (CCC) was the most enriched pathway followed by calcium signaling and mitogen-activated-kinase (MAPK) pathways. Notably, there was minimum overlap between components of the CCC pathway and other major enriched pathways in the network (Fig. 2A). Supplementary Figure 3 shows the identity of proteins in the BII that belong to the enriched pathways in Fig. 2.


A Rich-Club Organization in Brain Ischemia Protein Interaction Network.

Alawieh A, Sabra Z, Sabra M, Tomlinson S, Zaraket FA - Sci Rep (2015)

Venn Diagram of the distribution of BII proteins on different significantly enriched KEGG pathways.(A) Pathways with p-value less than 10^–12 are included. Complement and coagulation cascade (CCC) is the most enriched pathway and together with calcium signaling and MAPK signaling pathways form the three most significant pathways in our BII. Notably, Complement and Coagulation Pathway has little overlap in terms of components (4.4%) with other pathways compared to the latter two major pathways (22% and 48%). (B) Protein -protein interactions among the three most prominent pathways in the network. White dots indicate a node (protein) and edges indicate interactions. Red edges denote interactions that involve the CCC. Other edges are colored green. Despite the minimal intersection in terms of components between the CCC and other pathways, this cascade is still heavily interconnected with other prominent pathways in the network.
© Copyright Policy - open-access
Related In: Results  -  Collection

License
Show All Figures
getmorefigures.php?uid=PMC4550934&req=5

f2: Venn Diagram of the distribution of BII proteins on different significantly enriched KEGG pathways.(A) Pathways with p-value less than 10^–12 are included. Complement and coagulation cascade (CCC) is the most enriched pathway and together with calcium signaling and MAPK signaling pathways form the three most significant pathways in our BII. Notably, Complement and Coagulation Pathway has little overlap in terms of components (4.4%) with other pathways compared to the latter two major pathways (22% and 48%). (B) Protein -protein interactions among the three most prominent pathways in the network. White dots indicate a node (protein) and edges indicate interactions. Red edges denote interactions that involve the CCC. Other edges are colored green. Despite the minimal intersection in terms of components between the CCC and other pathways, this cascade is still heavily interconnected with other prominent pathways in the network.
Mentions: KEGG (Kyoto Encyclopedia of Genes and Genomes)14 pathway annotation revealed that complement and coagulation cascade (CCC) was the most enriched pathway followed by calcium signaling and mitogen-activated-kinase (MAPK) pathways. Notably, there was minimum overlap between components of the CCC pathway and other major enriched pathways in the network (Fig. 2A). Supplementary Figure 3 shows the identity of proteins in the BII that belong to the enriched pathways in Fig. 2.

Bottom Line: Functional annotation of the interactome uncovered prominent pathways and highlighted the critical role of the complement and coagulation cascade in the initiation and amplification of injury starting by activation of the rich-club.We performed an in-silico screen for putative interventions that have pleiotropic effects on rich-club components and we identified estrogen as a prominent candidate.Our findings show that complex network analysis of disease related interactomes may lead to a better understanding of pathogenic mechanisms and provide cost-effective and mechanism-based discovery of candidate therapeutics.

View Article: PubMed Central - PubMed

Affiliation: Department of Neurosciences, Medical University of South Carolina, Charleston, SC 29425.

ABSTRACT
Ischemic stroke involves multiple pathophysiological mechanisms with complex interactions. Efforts to decipher those mechanisms and understand the evolution of cerebral injury is key for developing successful interventions. In an innovative approach, we use literature mining, natural language processing and systems biology tools to construct, annotate and curate a brain ischemia interactome. The curated interactome includes proteins that are deregulated after cerebral ischemia in human and experimental stroke. Network analysis of the interactome revealed a rich-club organization indicating the presence of a densely interconnected hub structure of prominent contributors to disease pathogenesis. Functional annotation of the interactome uncovered prominent pathways and highlighted the critical role of the complement and coagulation cascade in the initiation and amplification of injury starting by activation of the rich-club. We performed an in-silico screen for putative interventions that have pleiotropic effects on rich-club components and we identified estrogen as a prominent candidate. Our findings show that complex network analysis of disease related interactomes may lead to a better understanding of pathogenic mechanisms and provide cost-effective and mechanism-based discovery of candidate therapeutics.

No MeSH data available.


Related in: MedlinePlus