Browsing by Author "Kural, Kamil Can"

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    A Machine Learning and Networks Approach to Infer Disease Mechanisms
    (2022) Kural, Kamil Can; Baranova, Ancha
    All biological problems, including cancer, mental disorders, rare diseases, and immunological disorders, are complex multisystem pathophysiological shifts facilitated by functional changes. Multiple points of origin and mechanisms can contribute, including genetic mutations, epigenetic factors, protein misfolding, and differential gene expression, which promote such functional abnormalities. This dissertation describes mega-analysis and machine learning methods to identify and select essential entities that are prime candidates for drivers of such disorganization. Furthermore, heterogeneous networks have been employed to achieve a more thorough pathway analysis that takes protein-protein interactions into account. This dissertation contains four projects, investigating PPARD’s role in major depressive disorder, exploring the link between schizophrenia and myocardial infarctions, identifying the connections between atopic dermatitis and major depressive disorder, and finally, biomarker identification for survival status prediction of patients with brain cancer.
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    Molecular Models of Aging: Comparative Analysis of Gene Signatures in Replicative Senescence and Stress Induced Premature Senescence
    Kural, Kamil Can; Kural, Kamil Can; Baranova, Ancha
    In culturing normal diploid cells, senescence may either happen naturally, in the form of replicative senescence, or it may be a consequence of external challenges such as oxidative stress. In this work, a comparative analysis design has been used that aims to reconstruct the molecular cascades which are specific for replicative senescence (RS) and stress-induced senescence (SIPS) in human fibroblasts. The results indicate the involvement of caspase-3/keratin-18 pathway and serine/threonine kinase Aurora A/ MDM2 pathway commonly shared between RS and SIPS. Moreover, stromelysin/MMP3 and N-acetyl glucosaminyl transferase enzyme MGAT1, which initiates the synthesis of hybrid and complex N-glycans, were identified as key orchestrating components in RS and SIPS, respectively. In RS only, Aurora-B driven cell cycle signaling was deregulated in concert with the suppression of anabolic branches of the fatty acids and estrogen metabolism. In SIPS, Aurora-B signaling is deprioritized, and the synthetic branches of cholesterol metabolism are upregulated, rather than downregulated, while proteasome/ubiquitin ligase pathways of protein degradation dominate the regulatory landscape. This picture indicates that SIPS proceeds in cells that are actively fighting stress which facilitates premature senescence while failing to completely activate the orderly program of RS. The promoters of genes differentially expressed in either RS or SIPS are unusually enriched by the binding sites for Homeobox family proteins, with particular emphasis on HMX1, IRX2, HDX and HOXC13. Additionally, Iroquois Homeobox 2 (IRX2) was identified as a master regulator for the secretion of SPP1-encoded Osteopontin, a stromal driver for tumor growth that is overexpressed by both RS and SIPS fibroblasts. The latter supports the hypothesis that senescence-specific de-repression of SPP1 aids in SIPS-dependent stromal activation.