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Stard5 and ADAM11 Marc Paul Waase Rockefeller University Digital Commons @ RU Student Theses and Dissertations 2009 An In Vivo Characterization of the Functional Role of Two Novel Genes: StARD5 and ADAM11 Marc Paul Waase Follow this and additional works at: http://digitalcommons.rockefeller.edu/ student_theses_and_dissertations Part of the Life Sciences Commons Recommended Citation Waase, Marc Paul, "An In Vivo Characterization of the Functional Role of Two Novel Genes: StARD5 and ADAM11" (2009). Student Theses and Dissertations. Paper 253. This Thesis is brought to you for free and open access by Digital Commons @ RU. It has been accepted for inclusion in Student Theses and Dissertations by an authorized administrator of Digital Commons @ RU. For more information, please contact [email protected]. AN IN VIVO CHARACTERIZATION OF THE FUNCTIONAL ROLE OF TWO NOVEL GENES: StARD5 AND ADAM11 A Thesis Presented to the Faculty of The Rockefeller University in Partial Fulfillment of the Requirements for the degree of Doctor of Philosophy by Marc Paul Waase June 2009 © Copyright by Marc Paul Waase, 2009 AN IN VIVO CHARACTERIZATION OF THE FUNCTIONAL ROLE OF TWO NOVEL GENES: StARD5 AND ADAM11 Marc Paul Waase, Ph.D. The Rockefeller University June 2009 Regulation of cholesterol levels within cells and organisms is crucial for their survival. Maintenance of cellular cholesterol homeostasis occurs mainly at the transcriptional level, via the Sterol Regulatory Element Binding Proteins (SREBP), the Liver X Receptors (LXR), and the Unfolded Protein Response (UPR)/ER Stress Response. This thesis attempts to characterize the in vivo physiological role of novel downstream target genes of these transcription factors: StARD5 and ADAM11. This thesis outlines the development and characterization of a floxed mouse allele of the UPR-upregulated, reticuloendothelial gene StARD5, as well as two different transgenic mouse lines, one which expresses the human StARD5 gene in the liver and one which expresses the human StARD5 in the reticuloendothelial system. We show that StARD5 plays an indispensable role in early embryogenesis since homozygous knockouts are not viable. Haploinsufficiency in the adult mouse does not alter plasma cholesterol or triglyceride levels, liver cholesterol levels, gallbladder bile composition, glucose tolerance, cholesterol efflux from macrophages, or atherosclerosis susceptibility. Two isoforms of the ADAM11 gene were identified, differing only in their cytoplasmic tails, with one highly expressed in the liver and the other highly expressed in the brain. The liver isoform of ADAM11 was induced by dietary cholesterol and the LXR transcription factor. In order to study the function of this gene, this thesis describes the development of a floxed mouse allele of ADAM11. Utilizing low and high cholesterol and cholic acid containing diets and the ADAM11 knockout, we did not find a phenotype for ADAM11 with respect to plasma cholesterol or triglyceride levels, liver lipid levels, gallbladder bile composition, glucose tolerance, or atherosclerosis susceptibility. We show that loss of ADAM11 in mice fed a high cholesterol diet lowers free plasma campesterol levels, without having an effect on total campesterol levels or other phytosterols. Using a yeast two-hybrid screen, we identified 3HAO as a putative ADAM11 cytoplasmic tail binding partner, which interacted non-specifically with the two cytoplasmic tail forms. ADAM11 knockout mice were previously shown to have a neurological phenotype to which we now add absence-like epilepsy. Finally, this thesis also outlines the development of a floxed mouse allele of the dietary cholesterol-downregulated, SREBP-upregulated liver gene StARD4; initial studies indicate that a full StARD4 knockout is viable. Dedicated to my wife, Cecilia, my mother, Danielle, and my father, Paul, for their unceasing and unconditional love, guidance, and support. Acknowledgments I want to express my deep gratitude to the many people who have helped to get me where I am today. First and foremost, I would like to thank my advisor Jan Breslow. I am grateful for the time I have spent in his lab. Jan is one of the nicest people whom I have ever gotten to know. He was a great mentor, allowing me to freely explore without putting too much pressure on me, knowing full well that I do that enough by myself. Jan was always there for me to discuss science and always offered words of encouragement. I am thankful for each and every member of the Breslow lab, past and present, for their help and friendship over the past four years. I want to thank Kara Maxwell for introducing me to the lab and getting me started. I want to thank particularly my campus-side bench-mates: Josh Riegelhaupt and Ralph Burckhardt, as well as my river-side lab-mates Kristine Nowak, Changcheng Zhao, and Jose Rodriguez, who over the past four years have been there to discuss ideas, scientific and not. I want to thank Helen Yu for all her work on sectioning my many mouse aortas. Our neighbors in the Stoffel and Strickland labs have also been extremely generous. I want to thank Matt Poy and Jan Kreutzfeldt in the Stoffel lab, who were more than willing to provide assistance and resources. I want to thank Erin Norris in the Strickland lab, who has also been extremely helpful. The Tri-Institutions have so many useful resources and so many kind people who have helped me, so I also want to thank Suzana Couto (SKI Pathology), Chingwen Yang (RU Gene Targeting), Rada Norinsky (RU Transgenics), and Connie Zhao (RU Genomics). I am also grateful for my classmates, the MD/PhD entering class of 2002, with whom I have been able to share the joys and the stresses of the past six years. My graduate career would not have run as smoothly without the help of everyone behind the scenes at the Deansʼ office at the Rockefeller Graduate School and the Cornell MD/PhD office. Marta, Kristen, Emily, Cristian, Sid, Renee, Elaine, Irma, Ruthie, and especially Olaf made sure that I could focus my full attention on science and my work. I thank my committee members: Sandy Simon, James Darnell, and Carl Blobel (HSS), for their advice and assistance over the past few years. I also thank a previous committee member Markus Stoffel, who got me started in science back when I was just a high school junior. I also want to thank my external committee iv member, Walter Miller (UCSF). I want to thank Eric Alani, my undergraduate research adviser, for his kindness and constant support. I never would have made it without the support and love from my family and friends. I want to thank my parents, Paul and Danielle Waase for their constant love, support and understanding. I want to thank my older sister Carine, who blazed a trail for me along this career path, always providing me with useful tips and ideas. I also want to thank my brother-in-law Sebastian and my new nephew/godson Julien, who has provided me with numerous fun breaks throughout my thesis writing. Finally, I would like to thank my best friend and my wife, Cecilia. Your constant support and understanding has been amazing, and your refreshing sense of humor always keeps me with a smile on my face. I cannot express how thankful I am that I have you in my life. v Table of Contents Dedication ................................................................................................... iii Acknowledgements .................................................................................... iv List of Figures ............................................................................................. x List of Tables ............................................................................................... xii List of Abbreviations .................................................................................. xiv Chapter 1: Introduction The Physiological and Pathophysiological Significance of Cholesterol ......... 1 Sources of Cholesterol: de novo Synthesis and Dietary Uptake ............... 2 Mouse as a Model Organism for Studying Cholesterol and Atherosclerosis....................................................................... 3 Cholesterol Regulation of Gene Expression ................................................. 4 The Sterol Regulatory Element Binding Proteins (SREBP) Pathway ....................................................................................... 5 The Liver X Receptor (LXR) Pathway and the Process of Reverse Cholesterol Transport (RCT) .......................................... 9 The Endoplasmic Reticulum Stress Response/ The Unfolded Protein Response .................................................. 15 Intracellular Cholesterol Transport ............................................................... 18 The Role of Nieman Pick C proteins ........................................................ 21 The Role of Oxysterol Binding Protein (OSBP)- related proteins (ORPs)................................................................. 22 The Role of Sterol Carrier Protein-2 (SCP-2) ......................................... 26 The Role of Caveolins .............................................................................. 28 The Role of Steroidogenic Acute Regulatory–Related Lipid Transfer Domain Protein Family ................................................................. 30 The StAR Subfamily ..................................................................... 30 The PCTP Subfamily ................................................................... 37 The RhoGap Subfamily ...............................................................
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