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Effect of 5-Ht on Cell Behaviour

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Effect of 5-Ht on Cell Behaviour Differential expression of C/T antigens and 5- HT receptors in Normotensive and Pre- eclamptic placentae, and their role in trophoblast invasion. A Thesis Submitted by Anushuya Priyadarshini Tamang To The Nottingham Trent University In requirement for the degree of Doctor of Philosophy April 2015 Copyright statement This work is the intellectual property of the author, and may also be owned by the research sponsor(s) and/or Nottingham Trent University. You may copy up to 5% of this work for private study, or personal, non-commercial research. Any re-use of the information contained within this document should be fully referenced, quoting the author, title, university, degree level and pagination. Queries or requests for any other use, or if a more substantial copy is required, should be directed in the first instance to the author. i Acknowledgements First of all I would like to thank my Director of Study, Dr.Shiva Sivasubramaniam for believing in me and giving me an opportunity to work on this project. I am grateful for your constant support, encouragement and some minor stress. I would also like to thank my supervisors Dr Morgan Geoffrey Mathieu and Professor Robert Rees for their valuable insight into this project. Next, I would like to thank my technical support team, Mike, Jackey and Dan, for always helping me with a smile and turning a blind eye to everything that went missing from their lab. (You know where to find them.) I am indebted to Gordan, for helping me through the painfully long hours of microscope settings and never complaining about it. Sincere thanks to Chris, Fiona, Carl and Gino for their valuable constructive criticisms and feedbacks on this work. I am grateful to Dr.Martin Gauster for being a perfect host during my study in Austria and for all the valuable tissue samples you have contributed to this study. To everyone who worked with me in ERD147A, past and present, Thank you! Especially to my labmate and sister, Reham, for hearing me out in times of trouble (especially from the panic attacks). I am also grateful to my colleagues, who I can proudly count on as my friends, Khdija, Biola, Mustafa, Salem, Wesam, Shweta, Sankalita, Yohanna, David and Naqash. A special thanks to Yvonne, my girl, for bearing with my insanity during write up. Lastly, I would like to thank my family and friends outside of the academia, for their constant love and support. Heet for always showing me the ‘Sunny’ side of life. Mom, Dad and my brothers- I can now say I have finally finished studying. Also, many thanks to my aunt, uncle and cousins for making me feel at home during my stay in UK. Special thanks (ευχαριστώ) to Stelios for your precious time and patience, which shall be repaid. To my close friends (Sharon, Yoel, Jimmy, Parth and Darshani), you guys can plan your trips now. I am grateful to you all for understanding my commitments and priorities. This would never have been possible without the love you all have showered on me. Thank you!! ii Dedicated to My beloved Grandpa (Memey) and Grandma (Mam)…. My heroes for lifetime My Dad (Apa) and Mom (Mommy)…. “No one can finish studying… One life is not enough to gather all the knowledge on this earth.” iii Table of contents LIST OF FIGURES .................................................................................................................... VIII LIST OF TABLES ........................................................................................................................ XII ABBREVIATIONS ..................................................................................................................... XIII ABSTRACT ................................................................................................................................... XV CHAPTER 1 INTRODUCTION .................................................................................................... 1 1.0 INTRODUCTION ....................................................................................................................... 2 PLACENTA .............................................................................................................................. 2 1.1.1 Formation of placenta (placentation) ........................................................................ 3 1.1.1.1 Ovulation to formation of blastocyst: ........................................................ 3 1.1.1.2 Implantation ............................................................................................... 4 1.1.1.3 Trophoblast differentiation ........................................................................ 4 1.1.2 Pregnancy stages and placental anatomy .................................................................. 7 1.1.2.1 First trimester (Week 1-13) ........................................................................ 7 1.1.2.2 Second trimester (Week 14-26) ................................................................. 8 1.1.2.3 Third trimester (Week 27 to 40) ................................................................ 8 1.1.3 Structure of full term placenta ................................................................................. 10 1.1.4 Function of placenta ................................................................................................ 10 1.1.5 Complications during placental development ......................................................... 11 1.2 TUMOUR ............................................................................................................................... 15 1.2.1 Hallmarks of cancer ................................................................................................ 15 1.3 PLACENTATION VS. TUMORIGENESIS ................................................................................... 19 1.3.1 Resemblance of placenta to tumour ........................................................................ 20 1.3.1.1 Cell invasion ............................................................................................ 20 1.3.1.2 High rate of cell proliferation .................................................................. 21 Avoiding apoptosis .................................................................................. 21 1.3.1.4 Escape from the immune system ............................................................. 22 1.3.1.5 ‘Pseudo-Vasculogenesis’ in placenta ....................................................... 22 1.3.1.6 Oncogenes in human placenta ................................................................. 22 1.3.2 Differences between placenta and tumour .............................................................. 24 1.4 NEW AVENUES FOR EXPLORATION ....................................................................................... 25 1.4.1 Expression of C/T antigens ..................................................................................... 25 1.4.1.1 Characteristics of C/T antigens ................................................................ 26 1.4.1.2 Functions of C/T antigens ........................................................................ 26 1.4.1.3 CT antigens of interest ............................................................................. 27 1.4.1.4 The importance of expression of C/T antigens in placenta ...................... 36 1.4.2 Expression of 5-HT receptor subtypes .................................................................... 36 1.4.2.1 Characteristic of 5-HT receptors .............................................................. 37 1.4.2.2 Different 5-HT receptor subtypes and their functions ............................. 38 1.4.2.3 5-HT receptors of interest ........................................................................ 38 1.4.2.4 Importance of expression of 5-HT receptors in placenta ......................... 44 1.4.3 Hypoxia and its relationship to invasion ................................................................. 45 1.4.3.1 Hypoxia during normal placentation ....................................................... 46 1.4.3.2 Hypoxia in cancer .................................................................................... 48 1.5 AIMS AND HYPOTHESIS ........................................................................................................ 50 CHAPTER 2 MATERIALS AND METHODS ........................................................................... 51 2.1 BUFFERS AND SOLUTIONS .................................................................................................... 52 2.2 ANTIBODIES.......................................................................................................................... 52 2.3 HUMAN PLACENTAL COLLECTION ........................................................................................ 53 2.4 TOTAL RNA EXTRACTION .................................................................................................... 53 2.5 CDNA TEMPLATE PREPARATION BY REVERSE TRANSCRIPTION .......................................... 54 2.6 GENE EXPRESSION STUDY .................................................................................................... 55 2.6.1 Primer designing and optimising ............................................................................. 55 2.6.2 Gene amplification using conventional PCR and gradient PCR ............................. 55 iv 2.6.3 Agarose gel electrophoresis .................................................................................... 56 2.6.4 Confirmation of the PCR products
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