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A network model of genomic hormone interactions underlying dementia and its translational validation through serendipitous off-target effect.

Younesi E, Hofmann-Apitius M - J Transl Med (2013)

Bottom Line: This model was evaluated for its biological and clinical relevance through pathway recovery test, evidence-based analysis, and biomarker-guided analysis.Translational validation of the model was performed using the proposed novel mechanism discovery approach based on 'serendipitous off-target effects'.Amongst these pathways, estrogen signaling pathway takes the major part in the model and insulin signaling pathway is analyzed for its association to learning and memory functions.

View Article: PubMed Central - HTML - PubMed

Affiliation: Department of Bioinformatics, Fraunhofer Institute for Algorithms and Scientific Computing-SCAI, Schloss Birlinghoven, Sankt Augustin 53754, Germany. erfan.younesi@scai.fraunhofer.de

ABSTRACT

Background: While the majority of studies have focused on the association between sex hormones and dementia, emerging evidence supports the role of other hormone signals in increasing dementia risk. However, due to the lack of an integrated view on mechanistic interactions of hormone signaling pathways associated with dementia, molecular mechanisms through which hormones contribute to the increased risk of dementia has remained unclear and capacity of translating hormone signals to potential therapeutic and diagnostic applications in relation to dementia has been undervalued.

Methods: Using an integrative knowledge- and data-driven approach, a global hormone interaction network in the context of dementia was constructed, which was further filtered down to a model of convergent hormone signaling pathways. This model was evaluated for its biological and clinical relevance through pathway recovery test, evidence-based analysis, and biomarker-guided analysis. Translational validation of the model was performed using the proposed novel mechanism discovery approach based on 'serendipitous off-target effects'.

Results: Our results reveal the existence of a well-connected hormone interaction network underlying dementia. Seven hormone signaling pathways converge at the core of the hormone interaction network, which are shown to be mechanistically linked to the risk of dementia. Amongst these pathways, estrogen signaling pathway takes the major part in the model and insulin signaling pathway is analyzed for its association to learning and memory functions. Validation of the model through serendipitous off-target effects suggests that hormone signaling pathways substantially contribute to the pathogenesis of dementia.

Conclusions: The integrated network model of hormone interactions underlying dementia may serve as an initial translational platform for identifying potential therapeutic targets and candidate biomarkers for dementia-spectrum disorders such as Alzheimer's disease.

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Related in: MedlinePlus

Elements of the seven hormonal signaling pathways form the core connected component of the brain interactome (normal state with all possible interactions). Pathway memberships are indicated by color codings; Green: estrogen signaling pathway; Red: insulin signaling pathway; Light blue: leptin signaling pathway; Dark blue: melatonin signaling pathway; Gray: thyroid signaling pathway; Brown: corticotropin-releasing hormone pathway. Yellow color indicates common membership to two or more pathways and also embeds the elements of the growth hormone signaling pathway.
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Figure 3: Elements of the seven hormonal signaling pathways form the core connected component of the brain interactome (normal state with all possible interactions). Pathway memberships are indicated by color codings; Green: estrogen signaling pathway; Red: insulin signaling pathway; Light blue: leptin signaling pathway; Dark blue: melatonin signaling pathway; Gray: thyroid signaling pathway; Brown: corticotropin-releasing hormone pathway. Yellow color indicates common membership to two or more pathways and also embeds the elements of the growth hormone signaling pathway.

Mentions: After the completion of this individual pathway recovery test, we aggregated all the elements of these seven pathways and mapped them onto the giant component of DHN. The aim was to detect the core of DHN where the majority of hormone cross talks occur. A subnetwork of 73 nodes and 133 edges was formed, representing the converged hormonal pathway interactions. Interestingly, 62 of these hormone peptides (ca. 86%) are densely interconnected and form the core of DHN. Besides, their interactions appeared to occur in different regions of the normal brain after adding the context of brain region annotations to each edge using the work of Bossi and Lehner (2009) (FigureĀ 3) [62]. Analysis of these annotations shows that the majority of the hormonal interactions occur in prefrontal cortex (ca. 93%), hypothalamus (ca. 92%) and cingulate cortex (ca. 90%), respectively (Additional file 6). The finding that interactions of the converged network mostly occur in prefrontal cortex and cingulate cortex is consistent with the neuroanatomical distribution of neurofibrillary tangles and plaques in the cerebral cortex of AD patients [63]. Moreover, the relevance of this finding to clinical attributes of the advanced AD pathology has been shown in several studies (Prefrontal cortex:[64,65]; Cingulate cortex:[66]; Hypothalamus:[67,68]). For example, it has been shown that prefrontal cortex, an important component for working memory, is the site of hormonal effects on cognition including estrogen [69], insulin [70], growth hormone [71], and thyroid hormone [72]. Thus, collective dysregulation of these pathways in prefrontal cortex of AD patients can lead to worsened memory impairment.


A network model of genomic hormone interactions underlying dementia and its translational validation through serendipitous off-target effect.

Younesi E, Hofmann-Apitius M - J Transl Med (2013)

Elements of the seven hormonal signaling pathways form the core connected component of the brain interactome (normal state with all possible interactions). Pathway memberships are indicated by color codings; Green: estrogen signaling pathway; Red: insulin signaling pathway; Light blue: leptin signaling pathway; Dark blue: melatonin signaling pathway; Gray: thyroid signaling pathway; Brown: corticotropin-releasing hormone pathway. Yellow color indicates common membership to two or more pathways and also embeds the elements of the growth hormone signaling pathway.
© Copyright Policy - open-access
Related In: Results  -  Collection

License
Show All Figures
getmorefigures.php?uid=PMC3733613&req=5

Figure 3: Elements of the seven hormonal signaling pathways form the core connected component of the brain interactome (normal state with all possible interactions). Pathway memberships are indicated by color codings; Green: estrogen signaling pathway; Red: insulin signaling pathway; Light blue: leptin signaling pathway; Dark blue: melatonin signaling pathway; Gray: thyroid signaling pathway; Brown: corticotropin-releasing hormone pathway. Yellow color indicates common membership to two or more pathways and also embeds the elements of the growth hormone signaling pathway.
Mentions: After the completion of this individual pathway recovery test, we aggregated all the elements of these seven pathways and mapped them onto the giant component of DHN. The aim was to detect the core of DHN where the majority of hormone cross talks occur. A subnetwork of 73 nodes and 133 edges was formed, representing the converged hormonal pathway interactions. Interestingly, 62 of these hormone peptides (ca. 86%) are densely interconnected and form the core of DHN. Besides, their interactions appeared to occur in different regions of the normal brain after adding the context of brain region annotations to each edge using the work of Bossi and Lehner (2009) (FigureĀ 3) [62]. Analysis of these annotations shows that the majority of the hormonal interactions occur in prefrontal cortex (ca. 93%), hypothalamus (ca. 92%) and cingulate cortex (ca. 90%), respectively (Additional file 6). The finding that interactions of the converged network mostly occur in prefrontal cortex and cingulate cortex is consistent with the neuroanatomical distribution of neurofibrillary tangles and plaques in the cerebral cortex of AD patients [63]. Moreover, the relevance of this finding to clinical attributes of the advanced AD pathology has been shown in several studies (Prefrontal cortex:[64,65]; Cingulate cortex:[66]; Hypothalamus:[67,68]). For example, it has been shown that prefrontal cortex, an important component for working memory, is the site of hormonal effects on cognition including estrogen [69], insulin [70], growth hormone [71], and thyroid hormone [72]. Thus, collective dysregulation of these pathways in prefrontal cortex of AD patients can lead to worsened memory impairment.

Bottom Line: This model was evaluated for its biological and clinical relevance through pathway recovery test, evidence-based analysis, and biomarker-guided analysis.Translational validation of the model was performed using the proposed novel mechanism discovery approach based on 'serendipitous off-target effects'.Amongst these pathways, estrogen signaling pathway takes the major part in the model and insulin signaling pathway is analyzed for its association to learning and memory functions.

View Article: PubMed Central - HTML - PubMed

Affiliation: Department of Bioinformatics, Fraunhofer Institute for Algorithms and Scientific Computing-SCAI, Schloss Birlinghoven, Sankt Augustin 53754, Germany. erfan.younesi@scai.fraunhofer.de

ABSTRACT

Background: While the majority of studies have focused on the association between sex hormones and dementia, emerging evidence supports the role of other hormone signals in increasing dementia risk. However, due to the lack of an integrated view on mechanistic interactions of hormone signaling pathways associated with dementia, molecular mechanisms through which hormones contribute to the increased risk of dementia has remained unclear and capacity of translating hormone signals to potential therapeutic and diagnostic applications in relation to dementia has been undervalued.

Methods: Using an integrative knowledge- and data-driven approach, a global hormone interaction network in the context of dementia was constructed, which was further filtered down to a model of convergent hormone signaling pathways. This model was evaluated for its biological and clinical relevance through pathway recovery test, evidence-based analysis, and biomarker-guided analysis. Translational validation of the model was performed using the proposed novel mechanism discovery approach based on 'serendipitous off-target effects'.

Results: Our results reveal the existence of a well-connected hormone interaction network underlying dementia. Seven hormone signaling pathways converge at the core of the hormone interaction network, which are shown to be mechanistically linked to the risk of dementia. Amongst these pathways, estrogen signaling pathway takes the major part in the model and insulin signaling pathway is analyzed for its association to learning and memory functions. Validation of the model through serendipitous off-target effects suggests that hormone signaling pathways substantially contribute to the pathogenesis of dementia.

Conclusions: The integrated network model of hormone interactions underlying dementia may serve as an initial translational platform for identifying potential therapeutic targets and candidate biomarkers for dementia-spectrum disorders such as Alzheimer's disease.

Show MeSH
Related in: MedlinePlus