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A NOVEL REGULATORY ROLE of TRAPPC9 in L-PLASTIN-MEDIATED ACTIN RING FORMATION and OSTEOCLAST FUNCTION a Thesis Submitted to K

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A NOVEL REGULATORY ROLE of TRAPPC9 in L-PLASTIN-MEDIATED ACTIN RING FORMATION and OSTEOCLAST FUNCTION a Thesis Submitted to K A NOVEL REGULATORY ROLE OF TRAPPC9 IN L-PLASTIN-MEDIATED ACTIN RING FORMATION AND OSTEOCLAST FUNCTION A Thesis submitted To Kent State University in partial fulfillment of the requirements for the degree of Master of Science by Nazar Jabbar Hussein December 2016 © Copyright All rights reserved Except for previously published materials Thesis written by Nazar J. Hussein B.Ed., University of Tikrit, Department of Biology, Samarra, Salah Addin, Iraq 2011 Approved by Dr. Fayez Safadi ______________________________, Chair, Master thesis Committee Dr. Denise Inman _______________________________, Members, Master thesis Committee Dr. Michael Model ______________________________, Accepted by Dr. Ernest J. Freeman ____________________________, Director, School of Biomedical Sciences Dr. James L. Blank _______________________________, Dean, College of Arts and Sciences TABLE OF CONTENTS TABE OF CONTE LIST OF vi LIST OF ABBREVIATION I. ABSTRAC II. III. MATERIALS AND METHODS IV. RESUL ..54 V. 77 VI. 82 VII. LITTERATE 85 LIST OF FIGURES Figure 1.1: |Schematic Diagram of Bone anatomy of Osteon ........8 Figure 1.2 I A model of osteoclast differentiation induced by stimulatory factors ......14 Figure 1.3: | Bone remodeling .......20 Figure 1.4: | Structural diagram representi Figure 1.5: | TRAPPC9 structur Figure 1.6: I Role of TRAPPC9 in intra-Golgi Figure 1.7: I Structural representation of osteoclast cytos Figure 1.8: I Schematic diagram of podosome Figure 1.9: | L- Figure 2. 1: | PMX vectro Figure 3.1: | TRAPPC9 expression increased during os Figure 3. 2: | Cathepsin.K and NFATc1 expression increased during osteoclast differentiat Figure 3. 3: | TRAPPC9 localization in p Figure 3. 4: | TRAPPC9 co-localizes with Cathepsin.K during OC differentiation Figure 3.5: | Figure 3.6: | Figure 3.7: | Figure 3.9: | LPL expression during osteocl Figure 3.10: | Assesment of TRAPPC9 overexpression transfuction and transduction Figure 3.11: | Assesment of TRAPPC9 overexpression transfuction and transduction Figure 3.12: | Assesment of TRAPPC9 overexpression transfuction and transduction Figure 3.13: | TRAPPC9 overexpression increases recruitment of LPL to Figure 3.14: | TRAPPC9 overexpression is not associated with LPL mRNA Figure 3.15: | TRAPPC9 overexpression enhanc Figure 3.16: | Mechanism of TRAPPC9/LPL bining and meadatign the actin podosomes/actin rign formation i LIST of TABLES Table 1: List of approved treatment for osteoporosis and its side Table 2: List of antibod Table 3: Osteoclast prim Table 4: LIST OF ABBREVIATIONS ALP Alkaline Phosphatase BMM Bone marrow macrophage OCN Osteocalcin OPG Osteoprotegrin OSX Osterix RANKL Receptor Activator of Nuclear factor-Kappa B ligand RUNX2 Runt-related Transcription Factor TRAPPC9 Trafficking Protein Particle Complex 9 TRAPP Transport Particle Protein LPL L-PLastin BMMs bone marrow-derived macrophages COPI coat Protein I OSCAR Osteoclast-associated immunoglobulin-like receptor NFATc1 Nuclear factor of activated T cells GEF Guanine Exchange Factors Ypt1p Yeast Protein Two 1 Protein TRAP Tartrate-Resistant Acid Phosphatase Dedication I would like to dedicate this study to my country, family, and to everyone who supported me during these years. To my father in his second death anniversary, I will be always as you wanted me to be, kind and successful. You always inspire me even though I cannot hear you or see you physically anymore. You will be always in my heart, mind, and prayers. and support despite of the long distance between us. To my brothers and sisters. Thank you for being there and thank you for all the advice and warm wishes. To all my friends from all over the world. Thank you for all your support, kind words, and great wishes. You are all so precious to me. To my advisor and mentor Dr. Fayez Safadi, without your wisdom, knowledge, and positive attitude, patience, and encouragement. Thank you for all the valuable experience that you have provided me during my training in your lab. To my lab members and colleagues: Asaad, thank you for all the delicious lunches that we had together, and the tremendous help and companionship as well. Greg, thank you for your willingness to help no matter what you were involved in, for your kindness and politeness. Tom, thank you for all your experience and precious notes. Fouad, thank you for all your kind words and your outgoing personality. Fatima, thank you for all the fine sweets and candies that you brought after each experiment. Kevin, thank you for all the help. Kim, thank you for being there where I needed help. Thank you all for being there when I needed someone to talk to and joke with. You are more than lab members; you are my best friends. - - - - - - - - - - - ur hypothesis is that TRAPPC9 plays a regulatory role in L-Plastin-mediated actin ring formation and osteoclast function and the overall objective of this research was to evaluate TRAPPC9/ LPL interaction as a possible target for modilities to enhance bone repair and regeneration. CHAPTER I INTRODUCTION The skeletal system is a complex and dynamic organ that undergo changes needed to maintain bone and calcium homeostasis through a process called bone remodeling. This process is crucial for repairing damaged bone and maintaining the homeostasis of minerals. This process is carried on through highly balanced function between local resorption of bone by the osteoclasts and bone formation by the osteoblasts. Indeed, an imbalance between these activities leads to and/or favors several diseases due either to an excess of bone resorption (e.g., osteoporosis, rheumatoid arthritis, and metastatic cancer) or bone deposition/formation (e.g., osteopetrosis and pycnodysostosis). The main forming cells are osteoblasts, which originate from the mesenchymal stem cell lineage. Osteoblasts produce a bone matrix that they later mineralized to form bone. Usually matured osteoblasts get trapped in the bone matrix and become osteocytes during the process of bone formation. Osteoclasts are polynucleated cells that are derived from the differentiation of monocyte/macrophage precursors close to the bone surface in response to two stromal hematopoietic factors, the receptor activator of nuclear-factor- (RANKL) and colony-stimulating factor-1 (CSF1). It has been shown that TRAPPC9, a newly identified protein of the TRAPP II complex 45, binds to -kB-inducing kinase (NIK), thus regulating both the canonical and alternate NF- Trafficking protein particle complex 9 (TRAPPC9) is a protein subunit of the Transport Protein Particle II (TRAPPII) and it plays an important role in endoplasmic reticulum (ER) exiting to Golgi complex, intra-Golgi, and endosome-to- Golgi transports in yeast cells 15, 74. Osteoclasts become polarized and undergo significant morphologic changes during differentiation into mature cells, which leads to the complete remodeling of the actin cytoskeleton and organization of the podosome contacts into a dense circumferential band of actin (a podosome ring). This ring will result in bone erosion by forming a tight adhesive contact (the sealing zone). The degradation products (both inorganic and organic) are taken up by the osteoclasts and further processed. The fully mature osteoclast can detach from the bone and move away from the resorption lacuna to participate in several rounds of resorption. Collectively, the integrity of the cytoskeleton depends on tightly regulated bone remodeling and is carried out according to the physiological needs of the organism8, 48 Our hypothesis was the focus of the study (chapter III), we showed that TRAPPC9 binds to LPL thus, TRAPPC9 overexpression promotes LPL recruitment to podosome/actin ring region during osteoclastogensis. To prove this hypostasis, we first sought to measure TRAPPC9 expression during osteogenic differentiation of bone marrow-derived macrophages (BMMs). Then, we investigated the potential role of TRAPPC9 in LPL-mediated actin ring formation and osteoclast function. Then we proposed a mechanism that could explain the Role of TRAPPC9 overexpression on osteoclast cytoskeleton organization by examining the physical binding between LPL and TRAPPC9. LPL was found to participate in early sealing zone formation of osteoclast. In addition, LPL has a role along with actin-binding protein cortactin, in the osteoclast sealing zone formation66. It has been shown that TRAPPC9 binds to several proteins such as TRAPPC10, TRAPPC2, and P150Glued a protein sub unit of Dynactin 113. In addition, TRAPPC9 was found to bind to COPI (coat Protein I). Therefore, we were interested to examine the potential role of TRAPPC9 in LPL- mediated actin ring formation and osteoclast function since our data approved the physical binding between TRAPPC9 and LPL. We were interested to examine the effect of TRAPPC9 overexpression on LPL recruitment to podosomes region. Such a recruitment may enhance the binding of LPL to F-actin thereby form stabilized podosomes. Skeleton The skeleton can be divided into two main structures: the appendicular skeleton, which is comprised of 139 bones, and the axial skeleton, which is comprised of 74 bones. Bones are generally grouped into four general categories: long bones, short bones, flat bones, and irregular bones. The long bones category involves the clavicle, humeri, radii, ulnae, metacarpals, femurs, tibia, fibulae, metatarsals, and phalanges. The short bones category involves the carpal and tarsal bones, patellae, and sesamoid bones. The flat bones category consists of the skull, mandible, scapulae, sternum, and ribs. Finally, the category of irregular
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