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UNIVERSITY of CALIFORNIA, SAN DIEGO Human Platelet Metabolic UNIVERSITY OF CALIFORNIA, SAN DIEGO Human Platelet Metabolic Network Reconstruction A Thesis submitted in partial satisfaction of the requirements for the degree Master of Science in Bioengineering by Sorena Rahmaniyan Committee in charge: Bernhard Ø. Palsson, Chair Marcos Intaglietta Geert W. Schmid-Schoenbein Neema Jamshidi 2011 Signature Page The Thesis of Sorena Rahmaniyan is approved and it is acceptable in quality and form for publication on microfilm and electronically: Chair University of California, San Diego 2011 iii DEDICATION I would like to dedicate this work to my parents, Hadigheh and Ghodrat, for always believing in me and supporting me through ups and downs of my life. I would also like to dedicate this work to all my friends and colleagues at the Baha’i Institute of Higher Education in Iran, who are discriminated and prevented from entering universities solely based on their believes. iv TABLE OF CONTENTS Signature Page ................................................................................................................... iii Dedication...……………………………………………..…………….………………….iv Table of Contents ................................................................................................................ v List of Figures ................................................................................................................... vii List of Tables ................................................................................................................... viii Acknowledgements ............................................................................................................ ix Abstract ............................................................................................................................... x 1. Introduction ..................................................................................................................... 1 1.1 Platelet ....................................................................................................................... 1 1.1.1 Platelet Biology: ................................................................................................. 1 1.1.2 Platelet Physiology and Function: ...................................................................... 2 1.1.3 Platelet Biochemistry: ......................................................................................... 3 1.1.4 Platelet Diseases: ................................................................................................ 3 1.2 Systems Biology ........................................................................................................ 4 1.2.1 An Integrative Approach .................................................................................... 4 1.2.2 Metabolic network reconstruction ...................................................................... 5 2. Omics Data Mining ......................................................................................................... 7 2.1 Introduction ............................................................................................................... 7 2.2 Methods ..................................................................................................................... 8 2.3 Results and Discussion .............................................................................................. 9 3. Bibliomics and Manual Curation .................................................................................. 16 3.1 Introduction ............................................................................................................. 16 3.2 Core Reactions ........................................................................................................ 17 3.3 Manual Curation ...................................................................................................... 17 3.3.1 Specific Reactions ............................................................................................ 17 3.3.2 Exchange Constraints ....................................................................................... 18 3.3.3 Functionality of the Recon1 ............................................................................. 18 3.4 Results and Discussion ............................................................................................ 19 4. Human Platelet Model .................................................................................................. 28 4.1 Introduction ............................................................................................................. 28 v 4.2 Final Reconstruction ............................................................................................... 28 4.3 Model content .......................................................................................................... 29 4.4 ModelFunctionality and Network Topology ........................................................... 32 4.5 Simulations .............................................................................................................. 39 4.6 Conclusion ............................................................................................................... 42 Appendix…………………………………………………………………………………43 References ......................................................................................................................... 87 vi LIST OF FIGURES Figure 1.1 TEM images of the human platelet showing some of the organelles in the cell. M: mitochondria, GL: glycogen, G: alpha granule, OCS: open canicular system, DB: dense body and MT: microtubules. ..................................................................................... 2 Figure 2.progress of proteomic studies on platelet over the past ten years. ..................... 12 Figure 3.translation of reported proteins from proteomics data into the reactions in recon1 was consistent across different studies. ............................................................................ 13 Figure 4. QC/QA of the proteomics data, by looking at the co-coverage of the proteomics datasets .............................................................................................................................. 14 Figure 5.The pathway analysis based of the proteomics data, the top 30 pathways that have been reported in the proteomics studies, ranked based on the number of the studies they were reported on and the number of proteins reported for each pathway. ................ 15 Figure 6. The well established platelet reactions in bibliomics, categorized into subsystems ........................................................................................................................ 26 Figure 7. the presence of the core reactions in bibliomics vs. proteomics ....................... 27 Figure 8. the source distribution of the reactions in the model ......................................... 31 Figure 9. The ranking distribution of the platelet model’s reactions ................................ 32 Figure 10.Network Connectivity, comparison of the connectivity of metabolites in the platelet model ( with connectivity of 10 and higher) with the same metabolite in the global model...................................................................................................................... 33 Figure 11. the contribution of Eigen modes to the reconstruction of the stoichiometric matrix which follows the power low ................................................................................ 34 Figure 12. FVA analysis of the model for all the reactions .............................................. 35 Figure 13. comparison of the coset lengths with different cut off thresholds for correlation criteria. .............................................................................................................................. 36 Figure 14. couple of the linear pathways picked up in the coset analysis of the model with correlation coefficient more than 0.95 .............................................................................. 37 Figure 15. Carbohydrate metabolism in platelet and its cosets ........................................ 38 Figure 16. Flux variability analysis of aspirin effect on platelet ...................................... 40 Figure 17.coset analysis of aspirin effect on platelet with a cut off value of 0.99 ........... 41 Figure 18.coset analysis of aspirin effect on platelet with a cut off value of 0.75 ........... 41 vii LIST OF TABLES Table 1.The proteomics data structure. ............................................................................... 9 Table 2. The annotation of proteomics studies used for human platelet reconstruction ... 10 Table 3. The summary of the proteomics data .................................................................. 12 Table 4. The core reactions (metabolic objectives) of human platelets, BCS: number of Biochemical Studies, NBCS: number of Non-Biochemical Studies, Prot: number of proteomics studies. The abundance of core reactions with no proteomics report is due to the platelet specific reactions with no GPR available for them, which lead to a miss connections of proteomics data and the reactions ............................................................. 19 Table 5. list of the platelet specific reactions added to Roecon1 in SimPheny ................ 21 Table 6. list of the platelet specific Metabolites added to Roecon1 in SimPheny ............ 23 Table 7. The exchange constraints
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