Coccolithophores are uni-cellular phytoplankton and they form an exceedingly diverse group in the phylum Haptophyta. They produce highly complex structures known as coccoliths by a biomineralisation process known as calcification. The first part of the work undertaken was to investigate the process of calcification in the coccolithophore Coccolithus pelagicus using a combination of Transmission Electron Microscopy (TEM), Scanning Electron Microscopy (SEM) and light microscopy techniques. This allowed better understanding of the formation, transit of the coccolith through the cell until its final placing in the coccosphere. The second part of the work looked at the coccolithophore Emiliania huxleyi which is divided into several morphotypes with the two most widely recognised being A and B, it can be further subdivided into further groups according to genotype by Coccolithophore Morphology Motif (CMM). The CMMs lie in the 3/ untranslated region of the coccolith-polysaccharide associated protein-GPA, which is associated with coccolith structure control and they are labelled I, II, III and IV. The work undertaken used a Scanning Electron Microscope (SEM) to investigate the morphologies of homozygous CMM I and CMMIV cell’s coccoliths. This information was used to establish a significant difference between the CMMI cells and CMMIV cells but only at certain locations. The cause for this is possibly as a result of several factors (temperature, salinity, pCO2, Ca availability and light levels) and requires further investigation.

Background: Disturbances in metabolic homeostasis, resulting in cardiovascular disease, are the major cause of morbidity and mortality in patients with chronic kidney disease (CKD). Mineral deposition in the vascular smooth muscle cell (VSMC)-rich medial layer of the vessel wall is a prominent driver of mortality in these patients. Vascular calcification (VC) is now recognized as an important predictor and independent risk factor for all-cause and cardiovascular mortality in patients with advanced CKD. Prolonged impairment in kidney functions, characteristic of chronic CKD, results in marked changes in blood biochemistry, namely elevated circulating levels of inorganic phosphate (Pi) and calcium. These changes in circulating mineral content trigger osteogenic transdifferentiation and apoptosis of the VSMCs, subsequently leading to VC. In addition to kidney-related metabolic changes, chronic inflammation and liver disease are also associated with increased VC. T-cell death-associated gene 51 (TDAG51) and growth differentiation factor 10 (GDF10) have been previously reported to contribute to metabolic regulation in conditions of atherogenic VC, osteogenesis, and adipogenesis. However their role in medial VC and associated morbidities remains unknown. Methods and Results: Using a combination of in vitro, ex vivo and in vivo models findings presented in this thesis demonstrate that TDAG51 is an important modulator of VC, and as such is upregulated by conditions of hyperphosphatemia. I show that VSMCs from TDAG51-/- mice exhibit reduced expression and activity of key driver of osteogenic transdifferentiation, Runt-related transcription factor 2 (Runx2). To explain these observations, I demonstrate reduced expression of type III sodium-dependent Pi transporter, Pit-1, as well as intracellular Pi in these cells. Additionally, GDF10, an established inhibitor of osteogenesis, was identified to be significantly upregulated in TDAG51-/- VSMCs and mice. In line with these observations, knockdown of human homologue of TDAG51, pleckstrin homology-like domain, family A, member 1, resulted in increased expression of GDF10. Consistent with the anti-osteogenic role of GDF10, treatment with recombinant human GDF10 reduced Pi-mediated hydroxyapatite deposition, Runx2 expression and activity in primary mouse VSMCs. Interestingly, GDF10-/- mice develop severe adiposity, hepatic lipid accumulation, injury and inflammation. To explain this phenotype, a marked increase in the expression and activity of established driver of adipogenesis, peroxisome-proliferator-activated receptor γ (PPAR γ) in the livers of GDF10-/- mice was demonstrated. Complementary experiments in cultured hepatocytes demonstrate that treatment with recombinant human GDF10 attenuates nuclear PPAR γ expression and subsequent lipid accumulation, inflammation and fibrosis in these cells. Conclusion: This work highlights TDAG51 as an important regulator of Pi-mediated VC through downregulation of Pit-1, Runx2, and GDF10. Additionally, GDF10 has been described as a novel systemic inhibitor and a potential diagnostic marker for VC. Lastly, this work further characterizes GDF10 as an adipokine important in the regulation of hepatic lipid levels, which can indirectly affect vascular health. / Thesis / Doctor of Philosophy (Medical Science)

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Thesis--PlanA (M.S.)--University of Wisconsin--Stout, 2003. / Includes bibliographical references.

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Typescript. / Thesis (Ph. D.)--University of Hawaii, 1966. / Bibliography: leaves [124]-130. / xiv, 130 leaves ill

Typescript. / Bibliography: leaves [280]-288. / xix, 288 l illus

Thesis (M.S.)--University of Michigan, Ann Arbor, 1970. / Typescript (photocopy). Includes bibliographical references (leaves 45-49). Also issued in print.