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A Genomics and Mathematical Modeling Approach for the Study Of A Genomics and Mathematical Modeling Approach for the study of Helicobacter pylori associated Gastritis and Gastric Cancer A dissertation submitted to the Graduate School of the University of Cincinnati in partial fulfillment of the requirements of degree of Doctor Of Philosophy in Systems Biology & Physiology Program in the Department of Molecular and Cellular Physiology by Shruti Marwaha Post Graduate Diploma in Bioinformatics, Institute of Bioinformatics and Applied Biotechnology, India, 2007 BSc. Zoology, University of Delhi, India, 2005 Committee Chair: Dr. Hamid Eghbalnia, Ph.D. Committee Members: Dr. Mario Medvedovic, Ph.D; Dr. Marshall Montrose, Ph.D; Dr. Nelson Horseman Ph.D; and Dr. Yana Zavros Ph.D 1 Abstract 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. 2 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 NFĸB, 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. 3 4 Acknowledgements I would like to acknowledge all the people in my professional and personal network for the scientific advice, support and encouragement I received during my PhD. First and foremost, I would like to thank my research advisor, Dr. Hamid Eghbalnia, for his inputs and insights through the development of this work, for the freedom to try different ideas. I wish to express my gratitude towards my thesis committee, Dr. Mario Medvedovic, Dr. Marshall Montrose, Dr. Nelson Horseman and Dr. Yana Zavros, who have helped greatly towards the refinement of this work through their reviews, inputs and suggestions. I am deeply grateful to them for agreeing to serve on my dissertation committee and for their advice and motivation. I am thankful to Dr. Zavros for her time, advice on the H. pylori and gastric cancer biology and giving me the opportunity for the hands-on experience in experimental lab. Many thanks to Dr. Medvedovic, for his suggestions, time and advice on statistics and his feedback on my ideas. I will also like to thank Dr. Montrose for his valuable advice, willingness to help & for being always accessible. It was a great experience studying in the Systems Biology and Physiology program at University of Cincinnati (UC). I wish to thank the Department and the University for the resources provided to me for my graduate studies. Completing Grad school would have not been possible without the support and motivation of family and friends. A special thanks to my friends at UC - Sayali, Ravi, Gopi and Balaji, for being the soundboard to my ideas. I am thankful to Mike and Mindy for helping me with my endeavor with wet lab. I big thank you to Priyanka, Divya, Swati, Preeti, Kavita, Hari, 5 Sudhir, Ganesh, Jai and all other friends from Cincy who made this place special. I am indebted to my parents and in-laws for their constant encouragement and support. I would like to dedicate this work to Maa - my mother, my support system, to my sister - Ritu didi, for her unconditional love and to my husband, my best friend - Ravi, without whose support this journey would neither be complete nor enjoyable. And last but not least, I would like to thank all the patients who kindly contributed their data to public repositories for biomedical research. 6 Table of Contents Chapter 1: Introduction and Motivation .............................................................................. 16 1.1 Gastric Cancer ........................................................................................................................................ 16 1.2 Objectives ................................................................................................................................................. 20 Chapter 2: Literature Review ................................................................................................... 21 2.1 Anatomy and Histology of Normal Stomach ............................................................................ 21 2.1.1 Anatomy ...................................................................................................................................... 21 2.1.2 Histology ..................................................................................................................................... 22 2.2 Gastric Cancer ........................................................................................................................................ 23 2.2.1 Classification of Gastric Cancer ......................................................................................... 23 2.2.2 Stages of Gastric Cancer ....................................................................................................... 24 2.2.3 Risk factors for Gastric Cancer .......................................................................................... 28 2.2.4 Gastric Cancer Diagnosis ..................................................................................................... 33 2.2.5 Currently Available Therapy for Gastric Cancer ....................................................... 34 2.3 Drug Repurposing: Finding new uses of old drugs ................................................................ 35 2.4 Mathematical Modeling .................................................................................................................... 36 2.4.1 Why mathematical models? ............................................................................................... 36 2.4.2 Modeling biology using Ordinary Differential Equations ...................................... 37 2.4.3 Using Eigenvalues to determine system’s stability .................................................. 39 Chapter 3: Mathematical model for studying Helicobacter pylori mediated inflammation in host gastric tissue. ....................................................................................... 41 3.1 Synopsis .................................................................................................................................................... 41 3.2 Background ............................................................................................................................................ 42 7 3.3 Aim .............................................................................................................................................................. 44 3.4 Methods .................................................................................................................................................... 44 3.4.1 Animal Model ............................................................................................................................ 44 3.4.2 Interaction Map ....................................................................................................................... 45 3.4.3 Statistical Analysis .................................................................................................................. 47 3.4.4 Mathematical model .............................................................................................................. 48 3.4.5 Sensitivity Analysis ................................................................................................................ 50 3.4.6 GEO Data ....................................................................................................................................
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