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A High-Throughput Screening Platform for in Vitro Elastic Fiber Washington University in St. Louis Washington University Open Scholarship Engineering and Applied Science Theses & McKelvey School of Engineering Dissertations Spring 5-15-2019 A High-Throughput Screening Platform for In Vitro Elastic Fiber Production and the Mass Transport Properties of the Elastic Fiber Compromised Arterial Wall Austin John Cocciolone Washington University in St. Louis Follow this and additional works at: https://openscholarship.wustl.edu/eng_etds Part of the Biomedical Engineering and Bioengineering Commons Recommended Citation Cocciolone, Austin John, "A High-Throughput Screening Platform for In Vitro Elastic Fiber Production and the Mass Transport Properties of the Elastic Fiber Compromised Arterial Wall" (2019). Engineering and Applied Science Theses & Dissertations. 443. https://openscholarship.wustl.edu/eng_etds/443 This Dissertation is brought to you for free and open access by the McKelvey School of Engineering at Washington University Open Scholarship. It has been accepted for inclusion in Engineering and Applied Science Theses & Dissertations by an authorized administrator of Washington University Open Scholarship. For more information, please contact [email protected]. WASHINGTON UNIVERSITY IN ST. LOUIS School of Engineering and Applied Science Department of Biomedical Engineering Dissertation Examination Committee: Jessica Wagenseil, Chair Kathy Flores Robert Mecham Lori Setton Jin-Yu Shao A High-Throughput Screening Platform for In Vitro Elastic Fiber Production and the Mass Transport Properties of the Elastic Fiber Compromised Arterial Wall by Austin Cocciolone A dissertation presented to The Graduate School of Washington University in partial fulfillment of the requirements for the degree of Doctor of Philosophy May 2019 Saint Louis, Missouri © 2019, Austin Cocciolone Table of Contents List of Figures................................................................................................................................ vi Acknowledgements....................................................................................................................... vii Abstract........................................................................................................................................ viii Chapter 1: Introduction ....................................................................................................................1 1.1 Motivation and Research Aims......................................................................................1 1.2 Summary of Chapters ....................................................................................................2 Chapter 2: Elastin, Arterial Mechanics, and Cardiovascular Disease .............................................4 2.1 Elastin ............................................................................................................................4 2.1.1 Elastin characterization...................................................................................4 2.1.2 Regulation of tropoelastin expression.............................................................5 2.1.3 Coacervation and crosslinking........................................................................6 2.1.4 Elastic fiber assembly .....................................................................................7 2.1.5 Elastolytic enzymes ........................................................................................7 2.2 Arterial Mechanics.........................................................................................................8 2.2.1 Arterial wall structure .....................................................................................8 2.2.2 The windkessel effect ...................................................................................10 2.2.3 Arterial stiffness and passive mechanical behavior ......................................11 2.2.4 Energy storage and return .............................................................................15 2.3 Elastin as a Signaling Molecule...................................................................................15 2.3.1 Tropoelastin ..................................................................................................15 ii 2.3.2 Elastin-derived peptides................................................................................16 2.3.3. Elastin receptor complex..............................................................................17 2.3.4 TGF-ß sequestration......................................................................................18 2.4 Cardiovascular Disease................................................................................................19 2.4.1 Genetic elastinopathies .................................................................................19 2.4.2 Mouse models of genetic elastinopathies .....................................................21 2.4.3 Effects of graded elastin amounts in mice ....................................................22 2.4.4 Acquired cardiovascular diseases .................................................................26 2.5 Tissue Engineering.......................................................................................................34 2.6 Summary and Future Directions ..................................................................................35 2.7 Acknowledgements......................................................................................................36 2.8 References....................................................................................................................37 Chapter 3: In Vitro Screening for Enhanced Elastic Fiber Crosslinking by Drugs and Small Molecules.......................................................................................................................................49 3.1 Introduction..................................................................................................................49 3.2 Methods........................................................................................................................56 3.2.1 Cell culture....................................................................................................56 3.2.2 Cell pellet hydrolysis ....................................................................................58 3.2.3 Competitive ELISA for desmosine quantitation...........................................58 3.2.4 Ninhydrin assay for total protein quantitation ..............................................60 3.2.5 Small molecule library NCI Diversity Set V ................................................60 3.2.6 Small molecule library primary screening....................................................61 3.2.7 Small molecule library hit selection and primary screen verification ..........61 3.2.8 Small molecule library secondary screening and replication .......................62 iii 3.3 Results..........................................................................................................................62 3.3.1 Time course in vitro elastic fiber synthesis...................................................62 3.3.2 ßAPN as an inhibition control.......................................................................63 3.3.3 DMSO cytotoxicity.......................................................................................63 3.3.4 Suitability of insulin and TGF-ß1 as positive controls .................................65 3.3.5 Suitability of antihypertensive drugs as positive controls ............................66 3.3.6 Primary screening .........................................................................................67 3.3.7 Secondary screening .....................................................................................70 3.4 Discussion....................................................................................................................71 3.5 Summary......................................................................................................................73 3.6 Limitations ...................................................................................................................75 3.7 Acknowledgments........................................................................................................75 3.8 References....................................................................................................................76 Chapter 4: Mass Transport in Arteries with Compromised Elastic Fibers ....................................78 4.1 Introduction..................................................................................................................78 4.2 Methods........................................................................................................................80 4.2.1 Transport theory............................................................................................80 4.2.2 Animal tissue preparation .............................................................................83 4.2.3 Experimental setup........................................................................................83 4.2.4 Elastase treatement........................................................................................84 4.2.5 Hydraulic conductance..................................................................................85 4.2.6 Solute flux.....................................................................................................86
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