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A Genomics and Mathematical Modeling Approach for the Study of Helicobacter Pylori associated Gastritis and Gastric Cancer

Marwaha, Shruti
http://orcid.org/0000-0002-9328-7164
http://rave.ohiolink.edu/etdc/view?acc_num=ucin1439308645

Abstract Details

2015, PhD, University of Cincinnati, Medicine: Systems Biology and Physiology.
Gastric cancer is the fifth most common malignancy in the world and third the leading cause of cancer-related mortality worldwide, with five-year survival rate of only 20-29%. In order to develop better drugs, diagnostics and preventive measures for gastric cancer, it is critical to understand the underlying molecular biology of the disease and factors that increase the risk for the disease. Helicobacter pylori-induced chronic gastritis is a major risk factor associated with gastric cancer development. We analyzed publically available gene expression data from patients with gastric cancer and patients with H. pylori mediated gastritis, to identify genes and pathways that play an important role in the two diseases. We further integrated the identified disease signature with Broad Institute’s Connectivity Map to identify and prioritize drugs that can potentially reverse the molecular signature of gastric cancer cells and that of gastric tumors resistant to Cisplatin-Flurouracil (CF) chemotherapy. Our analysis identified vorinostat, trichostatin A and thiostrepton as potential therapeutic compounds for gastric cancer treatment. We identified genes and pathways that are differentially expressed (57 up-regulated and 86 down-regulated) in both gastric cancer and H. pylori mediated atrophic gastritis. The topmost pathways enriched for these genes include - cell-cell adhesion/communication, tight junctions, leukocyte transendothelial migration, gastric acid secretion, potassium ion transport and creatine pathways. Analysis of CF resistant and sensitive tumors suggests the role of metabolic and statin pathways towards resistance to the chemotherapy. We also developed a mathematical model of a sub-network comprising of sonic hedgehog (SHH), pro-inflammatory cytokines and anti-inflammatory cytokines, which play a critical role in H. pylori mediated gastritis. We integrated qPCR results, mathematical modeling technique and microarray data from H. pylori infected mice to explore the temporal behavior of the cytokine-SHH sub-network. Our mathematical model suggests that NF?B, SHH and the cytokines engage in a feedback loop which can result in damped oscillations. The model helps to bring out emergent properties of the network and generate testable hypotheses. Future experiments capturing cytokines and SHH profile over time can reveal more insights about the relationship between the different genes, their regulation and improve our current understanding of the dynamics and sequence of the events in the system.
Nelson Horseman, Ph.D. (Committee Chair)
Mario Medvedovic, Ph.D. (Committee Member)
Marshall Montrose, Ph.D. (Committee Member)
Yana Zavros, Ph.D. (Committee Member)
Hamid Eghbalnia, Ph.D. (Committee Member)
133 p.
Bioinformatics

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Citations

  • Marwaha, S. (2015). A Genomics and Mathematical Modeling Approach for the Study of Helicobacter Pylori associated Gastritis and Gastric Cancer [Doctoral dissertation, University of Cincinnati]. OhioLINK Electronic Theses and Dissertations Center. http://rave.ohiolink.edu/etdc/view?acc_num=ucin1439308645

    APA Style (7th edition)

  • Marwaha, Shruti. A Genomics and Mathematical Modeling Approach for the Study of Helicobacter Pylori associated Gastritis and Gastric Cancer. 2015. University of Cincinnati, Doctoral dissertation. OhioLINK Electronic Theses and Dissertations Center, http://rave.ohiolink.edu/etdc/view?acc_num=ucin1439308645.

    MLA Style (8th edition)

  • Marwaha, Shruti. "A Genomics and Mathematical Modeling Approach for the Study of Helicobacter Pylori associated Gastritis and Gastric Cancer." Doctoral dissertation, University of Cincinnati, 2015. http://rave.ohiolink.edu/etdc/view?acc_num=ucin1439308645

    Chicago Manual of Style (17th edition)

ucin1439308645
1,008
© 2015, some rights reserved.Creative Commons License A Genomics and Mathematical Modeling Approach for the Study of Helicobacter Pylori associated Gastritis and Gastric Cancer by Shruti Marwaha is licensed under a Creative Commons Attribution-NonCommercial-NoDerivs 3.0 Unported License. Based on a work at etd.ohiolink.edu.
This open access ETD is published by University of Cincinnati and OhioLINK.