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Bibliography: leaves 86-103. Investigates the effect of zoledronic acid on myeloma cells and osteoblast-like cells to establish the molecular and cellular mechanisms responsible for the clinical effectiveness of bisphosphonates in the treatment of patients with myelomatosis. Concludes that zoledronic acid inhibits myelomatosis-induced osteolysis thorugh the mechanisms of myeloma cell death and proliferation and maturation of osteoblasts.

Addenda slip inserted in back. Includes bibliographical references (leaves 178-231). To further the understanding of the molecular mechanisms that contribute to the skeletal pathology of mucopolysaccharidosis type VI and to investigate the production of organic matrix by mucopolysaccharidosis VI osteoblasts

Addenda slip inserted in back. / Includes bibliographical references (leaves 178-231). / xiv, 234, [19] leaves, [56] leaves of plates : ill. (chiefly col.) ; 30 cm. / Title page, contents and abstract only. The complete thesis in print form is available from the University Library. / To further the understanding of the molecular mechanisms that contribute to the skeletal pathology of mucopolysaccharidosis type VI and to investigate the production of organic matrix by mucopolysaccharidosis VI osteoblasts / Thesis (Ph.D.)--University of Adelaide, Dept. of Paediatrics, 2001

Utilization of iron by hemoglobin-producing cells is highly efficient. The acquisition of iron from plasma requires the binding of diferric transferrin (Tf) to its cognate receptor (Tf-R) on the erythroid cell membrane, followed by internalization of the Tf - Tf-R complexes via receptor-mediated endocytosis. Through a poorly understood mechanism, iron is targeted to mitochondria, the site of heme biosynthesis. We believe that a direct interaction between iron-containing endosomes and mitochondria is essential for iron transfer to mitochondria and its efficient incorporation into heme. / In order to illustrate the interaction between endosomes and mitochondria, we have employed flow cytometry. Flow cytometry analysis of reticulocytes (erythrocyte precursors which still synthesize hemoglobin) stained with fluorescent dyes specific to mitochondria and endosomes revealed three distinct populations: mitochondria, endosomes and a population labeled with both dyes. This double-labeled population suggests a population composed of endosomes associated with mitochondria. Using non-fluorescent diferric-Tf, we were able to remove the double population, leaving only the endosomal and the mitochondrial population. This finding has confirmed that the double population is the result of the interaction between the two organelles. / Additionally, we established a cell-free assay consisting of fluorescent mitochondria and endosomes isolated from erythroid cells. Using confocal microscopy, we demonstrated a colocalization between the two organelles. We repeated the assay using fluorescent mitochondria and endosomes isolated from HeLa spinner cells. Using the mitochondrial uncoupler CCCP, we were able to significantly reduce the colocalization between the two organelles, indicating that the interaction between the organelles is specific and that the mitochondrial potential is a requirement for organellar interaction. / Based on our results from flow cytometry and confocal microscopy, we conclude that a specific and direct interaction exists between the two organelles.

Self-renewal is central to the expansion of normal and cancerous stem cells. Its understanding is therefore critical for future advances in transplantation-based therapies and cancer treatment. Although the molecular machinery controlling stem cell self-renewal remains poorly defined, a number of genes important to this process have recently been identified. Two prominent genes in this group are Hoxb4 and Bmi1. Members of our group led the way to demonstrate important regulatory functions of these genes in hematopoietic stem cell (HSC) self-renewal and expansion. / The major goal of my thesis project is to dissect mechanisms that regulate self-renewal of HSCs. Our starting hypothesis was that HSC activity is regulated by complementary and independent self-renewal mechanisms: self-renewal of expansion and self-renewal of maintenance (Chapters 1-2). In order to further verify this theory, we have analyzed the genetic interaction between Hoxb4 and Bmi1. While Hoxb4 overexpression triggers HSC expansion, Bmi1 proper expression is essential to sustain long-term stem cell activity. We have also demonstrated that Hoxb4 and Bmi1 regulate distinct gene targets, likely suggesting a complementary and independent function for these two regulators in HSC activity (Chapter 3). / The second part of this thesis highlights efforts that were made in order to get a better understanding of self-renewal mechanisms. We have identified potential new regulators of stem cell activity by characterizing a stem cell leukemia population (Chapter 4) and by assessing the expression of asymmetrical distributed factors (Chapter 5) and selected nuclear factors of the Hematopoietic Stem Cell Nuclear Factor Database (Chapter 6) in stem cell-enriched sub-fractions. / This project will lead to a better understanding of the cellular basis regulating self-renewal of both normal and cancer stem cells and potentially to the future identification of new self-renewal determinants.

Copies of author's previously published articles inserted. / Bibliography: leaves 89-126. / vii, 126, [88] leaves, [1] leaf of plates : ill. ; 30 cm. / Title page, contents and abstract only. The complete thesis in print form is available from the University Library. / Finds that the metabolism of substance P (SP) and the subsequent production of SP-(7-11) is important in regulating the biological activity of SP on chondrycytes in the synoviol joint. / Thesis (Ph.D.)--University of Adelaide, Dept. of Medicine, 1996?

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