OPEN STUDENT WEBINARS GEBZE TECHNICAL UNIVERSITY

Speaker : Dilara Uzuner

Title :Transcriptional landscape of cellular networks reveal interactions driving the dormancy mechanisms in cancer

Primary cancer cells exert unique capacity to disseminate and nestle in distant organs. Once seeded in secondary sites, cancer cells may enter a dormant state, becoming resistant to current treatment approaches, and they remain silent until they reactivate and cause overt metastases. To illuminate the complex mechanisms of cancer dormancy, 10 transcriptomic datasets from the literature enabling 21 dormancy–cancer comparisons were mapped on protein–protein interaction networks and gene-regulatory networks to extract subnetworks that are enriched in significantly deregulated genes. The genes appearing in the subnetworks and significantly upregulated in dormancy with respect to proliferative state were scored and filtered across all comparisons, leading to a dormancy–interaction network for the first time in the literature, which includes 139 genes and 1974 interactions. The dormancy interaction network will contribute to the elucidation of cellular mechanisms orchestrating cancer dormancy, paving the way for improvements in the diagnosis and treatment of metastatic cancer.

Speaker: Ecehan Abdik

Title: Systematic investigation of mouse models of Parkinson's disease by transcriptome mapping on a brain-specific genome-scale metabolic network

Genome-scale metabolic networks enable systemic investigation of metabolic alterations caused by diseases by providing interpretation of omics data. Although Mus musculus (mouse) is one of the most commonly used model organisms for neurodegenerative diseases, a brain-specific metabolic network model of mouse has not yet been reconstructed. Here we reconstructed the first brain-specific metabolic network model of mouse, iBrain674-Mm, by a homology-based approach, which consisted of 992 reactions controlled by 674 genes and distributed over 48 pathways. We validated the newly reconstructed network model by showing that it predicts healthy resting-state metabolic phenotypes of mouse brain compatible with literature. We later used iBrain674-Mm to interpret various experimental mouse models of Parkinson's Disease (PD) at the transcriptome level. To this aim, we applied a constraint-based modelling based biomarker prediction method called TIMBR (Transcriptionally Inferred Metabolic Biomarker Response) to predict altered metabolite productions from transcriptomic data. Systemic analysis of seven different PD mouse models by TIMBR showed that neuronal levels of glutamate, lactate, creatine phosphate, neuronal acetylcholine, bilirubin and formate increased in most of PD mouse models whereas levels of melatonin, epinephrine, astrocytic formate and astrocytic bilirubin decreased. Although most of the predictions were consistent with the literature, there were some inconsistencies among different PD mouse models, signifying that there is no perfect experimental model to reflect PD metabolism. The newly reconstructed brain-specific genome-scale metabolic network model of mouse can make important contributions to the interpretation and development of experimental mouse models of PD and other neurodegenerative diseases.

Speaker: Hatice Büşra Lüleci

Title: iMAT application as an integration method in Alzheimer's disease in order to predict reaction activity

Alzheimer's disease (AD) is the most common cause of dementia. There is increasing evidence of a possible link between the incidence and progression of AD and metabolic dysfunction. Determining the changes in the activity of metabolic pathways should be a major interest in the treatment of AD. Mapping sample-based gene expression levels by using Integrative Metabolic Analysis Tool (iMAT) optimization algorithm on Human-GEM led to personalized metabolic networks. Each personalized metabolic network for healthy and disease cases has a different number of reactions and genes. This variation across personalized models reveals the inherent heterogeneity of control and AD samples and justifies our personalized approach. Reactions in each model were converted to binary vectors. This categorized data was analyzed by performing Fisher-Exact test. Based on these calculations, significantly changed reactions and pathways were detected. Mapping biochemical alterations associated with AD is crucial to fill knowledge gaps on the disease mechanisms.

Speaker: Müberra Fatma Cesur

Title: Network-based metabolism-centered screening of potential drug targets in Klebsiella pneumoniae at genome scale

Klebsiella pneumoniae is an opportunistic bacterial pathogen leading to life-threatening nosocomial infections. Emergence of highly resistant strains poses a major challenge in the management of the infections by healthcare-associated K. pneumoniae isolates. Thus, despite intensive efforts, the current treatment strategies remain insufficient to eradicate such infections. Failure of the conventional infection-prevention and treatment efforts explicitly indicates the requirement of new therapeutic approaches. This prompted us to systematically analyze the K. pneumoniae metabolism to investigate drug targets. Genome-scale metabolic networks (GMNs) facilitating the systematic analysis of the metabolism are promising platforms. Thus, we used a GMN of K. pneumoniae MGH 78578 to determine putative targets through gene- and metabolite-centric approaches. To develop more realistic infection models, we performed the bacterial growth simulations within different host-mimicking media, using an improved biomass formation reaction. We selected more suitable targets based on several property-based prioritization procedures. KdsA was identified as the high-ranked putative target satisfying most of the target prioritization criteria specified under the gene-centric approach. Through a structure-based virtual screening protocol, we identified potential KdsA inhibitors. In addition, the metabolite-centric approach extended the drug target list based on synthetic lethality. This revealed the importance of combined metabolic analyses for a better understanding of the metabolism. To our knowledge, this is the first comprehensive effort on the investigation of the K. pneumoniae metabolism for drug target prediction through the constraint-based analysis of its GMN in conjunction with several bioinformatic approaches. This study can guide the researchers for the future drug designs by providing initial findings regarding crucial components of the Klebsiella metabolism.