Genetic Signatures for a Rodent Model of Parkinson's Disease Using Combinatorial Optimization Methods

Hourani, Mou'ath; Berretta, Regina; Mendes, Alexandre; Moscato, Pablo

doi:10.1007/978-1-60327-429-6_20

Cited by 15 publications

(9 citation statements)

References 30 publications

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“…More details are provided in the Materials and Methods section. This methodology has been used to identify robust gene sets associated to a variety of diseases, including Alzheimer's [89], [91], Parkinson's [92], and prostate cancer [93]. Gene sets obtained by this methodology maximise intra-class coherency and inter-class discriminatory power with the minimum number of genes[94].…”

Section: Resultsmentioning

confidence: 99%

A Transcription Factor Map as Revealed by a Genome-Wide Gene Expression Analysis of Whole-Blood mRNA Transcriptome in Multiple Sclerosis

et al. 2010

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BackgroundSeveral lines of evidence suggest that transcription factors are involved in the pathogenesis of Multiple Sclerosis (MS) but complete mapping of the whole network has been elusive. One of the reasons is that there are several clinical subtypes of MS and transcription factors that may be involved in one subtype may not be in others. We investigate the possibility that this network could be mapped using microarray technologies and contemporary bioinformatics methods on a dataset derived from whole blood in 99 untreated MS patients (36 Relapse Remitting MS, 43 Primary Progressive MS, and 20 Secondary Progressive MS) and 45 age-matched healthy controls.Methodology/Principal FindingsWe have used two different analytical methodologies: a non-standard differential expression analysis and a differential co-expression analysis, which have converged on a significant number of regulatory motifs that are statistically overrepresented in genes that are either differentially expressed (or differentially co-expressed) in cases and controls (e.g., V$KROX_Q6, p-value <3.31E-6; V$CREBP1_Q2, p-value <9.93E-6, V$YY1_02, p-value <1.65E-5).Conclusions/SignificanceOur analysis uncovered a network of transcription factors that potentially dysregulate several genes in MS or one or more of its disease subtypes. The most significant transcription factor motifs were for the Early Growth Response EGR/KROX family, ATF2, YY1 (Yin and Yang 1), E2F-1/DP-1 and E2F-4/DP-2 heterodimers, SOX5, and CREB and ATF families. These transcription factors are involved in early T-lymphocyte specification and commitment as well as in oligodendrocyte dedifferentiation and development, both pathways that have significant biological plausibility in MS causation.

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Section: Resultsmentioning

confidence: 99%

A Transcription Factor Map as Revealed by a Genome-Wide Gene Expression Analysis of Whole-Blood mRNA Transcriptome in Multiple Sclerosis

et al. 2010

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“…Enhanced levels of STK35 have been reported in tissues obtained from colorectal cancer patients (30) and shown to be altered in a rodent model of Parkinson disease (31). Additionally, VEGF stimulates STK35 expression in endothelial cells (15).…”

Section: Discussionmentioning

confidence: 99%

Enhanced Cardiac Regenerative Ability of Stem Cells After Ischemia-Reperfusion Injury

Joladarashi

Garikipati

Thandavarayan

et al. 2015

Journal of the American College of Cardiology

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Background Micro ribonucleic acid (miR) dysregulation in the myocardium has been implicated in cardiac remodeling after injury or stress. Objectives This study sought to explore the role of miR in human CD34+ cell (hCD34+) dysfunction in vivo after transplantation into the myocardium under ischemia-reperfusion (I-R) conditions. Methods In response to inflammatory stimuli, the miR array profile of endothelial progenitor cells (EPC) was analyzed using a polymerase chain reaction-based miR microarray. MiR-377 expression was assessed in myocardial tissue from human patients with heart failure (HF). We investigated the effect of miR-377 inhibition on hCD34+ cell angiogenic proteome profile, in vitro and on cardiac repair and function after I-R injury in immunodeficient mice. Results The miR array data from EPCs in response to inflammatory stimuli indicate changes in numerous miR with a robust decrease in miR-377. Human cardiac biopsies from HF patients showed significant increase in miR-377 expression compared to nonfailing control hearts. Proteome profile of hCD34+ cells transfected with miR-377 mimics showed significant decrease in proangiogenic proteins versus nonspecific control transfected cells. We also validated that serine/threonine kinase 35 is a target of miR-377 using a dual-luciferase reporter assay. In a mouse model of myocardial I-R, intramyocardial transplantation of miR-377-silenced hCD34+ cells in immunodeficient mice, promoting neovascularization (at 28 days, post-I-R) and lower interstitial fibrosis, leading to improved left ventricular (LV) function. Conclusions These findings indicate that HF increases miR-377 in the myocardium, which is detrimental to stem cell function, and transplantation of miR-377 knockdown hCD34+ cells into ischemic myocardium promoted their angiogenic ability, attenuating LV remodeling and cardiac fibrosis.

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“…We solve an instance of this problem numerically using an integer programming formulation. This approach has been previously employed to obtain molecular biomarker signatures in Alzheimer's Disease [1], [629], models of Parkinson disease [630], prostate cancer [631], electrode selection in EEGs [632], and elsewhere. To obtain mathematically proven optimal solutions of the integer programming formulation, the CPLEX commercial optimization solver was used.…”

Section: Methodsmentioning

confidence: 99%

Uncovering Molecular Biomarkers That Correlate Cognitive Decline with the Changes of Hippocampus' Gene Expression Profiles in Alzheimer's Disease

et al. 2010

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BackgroundAlzheimer's disease (AD) is characterized by a neurodegenerative progression that alters cognition. On a phenotypical level, cognition is evaluated by means of the MiniMental State Examination (MMSE) and the post-morten examination of Neurofibrillary Tangle count (NFT) helps to confirm an AD diagnostic. The MMSE evaluates different aspects of cognition including orientation, short-term memory (retention and recall), attention and language. As there is a normal cognitive decline with aging, and death is the final state on which NFT can be counted, the identification of brain gene expression biomarkers from these phenotypical measures has been elusive.Methodology/Principal FindingsWe have reanalysed a microarray dataset contributed in 2004 by Blalock et al. of 31 samples corresponding to hippocampus gene expression from 22 AD subjects of varying degree of severity and 9 controls. Instead of only relying on correlations of gene expression with the associated MMSE and NFT measures, and by using modern bioinformatics methods based on information theory and combinatorial optimization, we uncovered a 1,372-probe gene expression signature that presents a high-consensus with established markers of progression in AD. The signature reveals alterations in calcium, insulin, phosphatidylinositol and wnt-signalling. Among the most correlated gene probes with AD severity we found those linked to synaptic function, neurofilament bundle assembly and neuronal plasticity.Conclusions/SignificanceA transcription factors analysis of 1,372-probe signature reveals significant associations with the EGR/KROX family of proteins, MAZ, and E2F1. The gene homologous of EGR1, zif268, Egr-1 or Zenk, together with other members of the EGR family, are consolidating a key role in the neuronal plasticity in the brain. These results indicate a degree of commonality between putative genes involved in AD and prion-induced neurodegenerative processes that warrants further investigation.

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Genetic Signatures for a Rodent Model of Parkinson's Disease Using Combinatorial Optimization Methods

Cited by 15 publications

References 30 publications

A Transcription Factor Map as Revealed by a Genome-Wide Gene Expression Analysis of Whole-Blood mRNA Transcriptome in Multiple Sclerosis

A Transcription Factor Map as Revealed by a Genome-Wide Gene Expression Analysis of Whole-Blood mRNA Transcriptome in Multiple Sclerosis

Enhanced Cardiac Regenerative Ability of Stem Cells After Ischemia-Reperfusion Injury

Uncovering Molecular Biomarkers That Correlate Cognitive Decline with the Changes of Hippocampus' Gene Expression Profiles in Alzheimer's Disease

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