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Gene Expression in the Peripartum Canine Placenta

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Gene Expression in the Peripartum Canine Placenta AN ABSTRACT OF THE THESIS OF Elizabeth Jane Fellows for the degree of Master of Science in Animal Sciences presented on August 30, 2012 Title: Gene Expression in the Peripartum Canine Placenta Abstract Approved: Michelle A. Kutzler This research investigated gene expression in the canine placenta during the peripartum period. Previous studies have recognized molecular changes that occur in the placenta around the time of placental release in other species, but no study has looked at gene expression in the late gestation canine placenta. Of particular significance for this thesis work is the groundwork laid for future studies modeling placental abnormalities in dogs (e.g. subinvolution of placental sites) and humans (e.g. preeclampsia, placenta accreta). Despite years of research in multiple species, the exact mechanisms and processes regulating trophoblast invasion and placental release remain unclear. Therefore, the specific objective of this research was to characterize gene expression changes that occur during the peripartum period in the dog using microarray and real-time RT-PCR. Following total RNA isolation, the microarray analysis was performed by hybridizing total RNA to the Canine 2.0 Array (Affymetrix, Santa Clara, CA). Microarray analysis was carried out using the limma and affy packages through the Bioconductor software in WKH5VWDWLVWLFDOHQYLURQPHQW'LIIHUHQWLDOH[SUHVVLRQZDVGHILQHGDVS)'5S DQGDORJIROGFKDQJHRI)ROORZLQJF'1$V\QWKHVLVUHDO-time RT-PCR was performed using TaqMan primer and probes that were pre-made and pre-optimized for canine tissues (Applied Biosystems, Carlsbad, CA). Microarray analysis showed differential expression in 18 genes between pre-term and pre-labor sample groups, 38 genes that were differentially expressed between pre-term and parturient samples and no genes that were differentially expressed between pre-labor and parturient samples. Microarray analysis led to the identification of several candidate genes for closer investigation using real-time RT-PCR. These genes included MMP-1, MMP-2, MMP-9, TIMP-2, VEGF-A, Flt-1, CD44, DAG-1, IL-6 and CXCL10. All of these genes have been linked to trophoblast invasion or regression or placental release in a number of species including humans, cattle and rodents. Using real-time RT-PCR, there was a significant difference in MMP-9 mRNA expression in pre-term samples compared to pre- labor and parturient samples (p<0.05). However, there was no significant difference in mRNA expression of MMP-2, TIMP-2, VEGF-A, Flt-1 CD44, DAG-1, IL-6 or CXCL10. Future studies may focus on additional candidate genes identified by microarray that play a role in tissue remodeling at the end of canine gestation such as IL-8, EPHX2, PI3 and SERPINE1. ©Copyright by Elizabeth Jane Fellows August 30, 2012 All Rights Reserved Gene Expression in the Peripartum Canine Placenta by Elizabeth Jane Fellows A THESIS submitted to Oregon State University in partial fulfillment of the requirements for the degree of Master of Science Presented August 30, 2012 Commencement June 2013 Master of Science thesis of Elizabeth Jane Fellows presented on August 30, 2012. APPROVED: Major Professor representing Animal Sciences Head of the Department of Animal and Rangeland Sciences Dean of the Graduate School I understand that my thesis will become part of the permanent collection of Oregon State University libraries. My signature below authorizes release of my thesis to any reader upon request. Elizabeth Jane Fellows, Author ACKNOWLEDGEMENTS I thank my advisor, Dr. Michelle Kutzler, for her invaluable guidance during my graduate studies at Oregon State University. Her dedication to my success as a graduate student has been beyond compare. Dr. Kutzler’s drive and confidence in me has helped me to accomplish my goals. I also thank Dr. Tim Hazzard for his assistance in sample collection and willingness to provide advice throughout my graduate career. I would also like to thank the other graduate students in the Theriogenology Laboratory: Laura Sahlfeld, Justine Gullaba and Caitlin Donovan for making the challenges of graduate school much more enjoyable and helping me always see the positive side of things. Furthermore, I would like to acknowledge a few people who helped make this research possible. I would like to acknowledge Dr. Howard Meyer and Dr. Cheryl Lopate, who were very accommodating during tissue collections. I would like to thank Anne-Marie Girard for her help with microarray. I would also like to thank Dr. Gerd Bobe and Dr. Yanming Di for their assistance with microarray analysis and overall statistics. Many thanks go out to my family for their unwavering support over the years. I am very fortunate to have two supportive parents, Jane and Roger Fellows who have always encouraged me through every challenge I have chosen to take on. Also, many thanks go to my siblings Caitlin, Jim and Andrew for reminding me to never take life too seriously. I would also like to thank my long-time boyfriend Bates Tillman, for his steadfast support, encouragement and constant positivity throughout my graduate career. Lastly, I would like to thank everyone in the Department of Animal and Rangeland Sciences. I have had a wonderful experience here at Oregon State University and this has been a direct result of the people I have met in this department. CONTRIBUTIONS OF AUTHORS Dr. Timothy Hazzard assisted in the collection of placentas and edited the manuscript. Lauren Watson assisted in the analysis of microarray data and edited the manuscript. Justine assisted in the isolation of trophoblasts and edited the manuscript. TABLE OF CONTENTS Page 1 INTRODUCTION .....................................................................................................1 1.1 Genetic Regulation of Trophoblast Invasion and Migration .........................1 1.1.1 Significance..................................................................................1 1.1.2 Summary ......................................................................................1 1.1.3 Matrix Metalloproteinases and their Tissue Inhibitors ................2 1.1.4 KiSS-1 and its Receptor KiSS-1R ...............................................4 1.1.5 Vascular Endothelial Growth Factor and its receptor Flt-1 .........5 1.1.6 Interleukins ..................................................................................6 1.1.7 Integrins .......................................................................................8 1.1.8 Urokinase-type Plasminogen Activator and Plasminogen ...........8 1.1.9 Other Important Factors ...............................................................9 1.1.10 Conclusion ...................................................................................11 1.2 Genetic Regulation of Trophoblast Regression and Placental Release at Parturition .....................................................................................12 1.2.1 Significance..................................................................................12 1.2.2 Summary ......................................................................................12 1.2.3 Matrix Metalloproteinases and their Tissue Inhibitors ................13 1.2.4 KiSS-1 and its Receptor KiSS-1R ...............................................14 1.2.5 Other Important Factor ................................................................14 1.2.6 Conclusion ...................................................................................15 1.3 Genes Involved in Carnivore Implantation, Placental Development and Parturition ................................................................................................16 1.3.1 Summary ......................................................................................16 1.3.2 Canine Uterine and Placental Gene Expression ...........................16 1.3.3 Placental Gene and Protein Expression in other Carnivores .......................................................................20 1.3.4 Conclusion ...................................................................................21 TABLE OF CONTENTS (Continued) Page 1.4 References ......................................................................................................22 2 GENE EXPRESSION IN PRE-TERM, PRE-LABOR AND PARTURIENT CANINE PLACENTA .....................................................................33 2.1 Introduction ....................................................................................................33 2.2 Materials and Methods ...................................................................................34 2.2.1 Tissue Collection .........................................................................34 2.2.2 RNA Isolation ..............................................................................35 2.2.3 TaqMan Real-Time RT-PCR .......................................................35 2.2.4 Statistical Analysis .......................................................................36 2.3 Results ............................................................................................................39 2.4 Discussion ......................................................................................................41 2.5 References ......................................................................................................44 3 INVESTIGATING THE CANINE PLACENTAL TRANSCRIPTOME IN THE PERIPARTUM PERIOD .............................................................................46 3.1 Introduction ....................................................................................................46
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