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Amylin is a 37 amino acid long peptide that aggregates into toxic oligomers and fibrils. Since amylin is secreted by and also acts on pancreatic beta cells, type II diabetes is classified as an amyloidogenic disease. This study focuses on the development of a cost effective chemical synthetic strategy for amylin synthesis as previous studies relied on extremely expensive pseudoproline derivatives. Furthermore, commercially available amylin varies between batches and also contains impurities that could generate anomalies and affect reproducibility of experiments. Secondly, chemically synthesized non-methylated and N-methylated derivatives of amylin were shown to inhibit toxicity of full length amylin. A fluorescentlylabeled chemically synthesized derivative of amylin was used to track cellular localization of amylin via confocal microscopy. Amylin aggregation kinetics was established using a surface plasmon resonance (SPR) biosensor. In addition, nanoparticle tracking analysis (NTA) was used as a novel technique to determine the size of oligomers over real time. This technology indicated that the size range of the toxic species of amylin is between 200-300 nm. Furthermore, it can be suggested that NTA could potentially be developed into a screening tool for inhibitors of amylin-mediated cytotoxicity. / Thesis (Ph.D.)-University of KwaZulu-Natal, Westville, 2012.

Thesis (M.S.)--University of Nevada, Reno, 2006. / "August, 2006." Includes bibliographical references (leaves 112-116). Library also has microfilm. Ann Arbor, Mich. : ProQuest Information and Learning Company, [200x]. 1 microfilm reel ; 35 mm. Online version available on the World Wide Web.

Diss. (sammanfattning) Stockholm : Karol. inst., 2005. / Härtill 5 uppsatser.

Thesis (M.A.)--Baylor University, 2007. / Includes bibliographical references (p. 34-38).

Thesis (Ph.D.) -- University of Rhode Island, 2008. / Typescript. Includes bibliographical references (leaves 227-239).

Thesis (Ph.D)--Chemistry and Biochemistry, Georgia Institute of Technology, 2009. / Committee Chair: Dr. Sheldon W. May; Committee Member: Dr. James C. Powers; Committee Member: Dr. Nicholas Hud; Committee Member: Dr. Niren Murthy; Committee Member: Dr. Stanley H. Pollock. Part of the SMARTech Electronic Thesis and Dissertation Collection.

Diss. (sammanfattning) Stockholm : Karolinska institutet, 2006. / Härtill 4 uppsatser.

published_or_final_version / Zoology / Doctoral / Doctor of Philosophy

The mechanism of action of insulin and epidermal growth factor was studied by genetic and biochemical means. Particular emphasis was placed on the ability of these factors to induce DNA synthesis and the relationship of endocytosis to that ability. Insulin was crosslinked to the active fragment A of diphtheria toxin. This conjugate specifically killed cultured mouse cells through an insulin receptor-mediated process. The conjugate was used to select genetic variants resistant to its cytotoxic effect. Six resistant variants were isolated, 2 of which retained very low insulin receptor activity. When these two variants were further analyzed both displayed altered cell shape and growth properties. The CI-3 variant also was shown to have a deficient lysosomal system and failed to efficiently degrade epidermal growth factor. This variant was, however, fully responsive to the mitogenic action of EGF. This suggested that lysosomal processing is unimportant in the production of a mitogenic stimulus by EGF. EGF was found to be endocytosed by fibroblasts through 2 separate pathways. One pathway involves an unidentified organelle and correlated with increased degradation of the ligand. The other pathway involves a Golgi-like component and is correlated with a lack of degradation and uptake into a dense, non-lysosomal organelle. Uptake of EGF into this non-lysosomal component, which we named mitosomes, correlated with the ability of EGF to induce DNA synthesis. From these results, a model was constructed for the coupling of endocytosis, uptake into mitosomes and the stimulation of DNA synthesis.