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Understanding the structure, toxicity and inhibition of IAPP at the nanoscale
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Pilkington, Emily H. (2019) Understanding the structure, toxicity and inhibition of IAPP at the nanoscale. PhD thesis, University of Warwick.
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Official URL: http://webcat.warwick.ac.uk/record=b3520170~S15
Abstract
The aggregation of peptides or proteins to form amyloid fibrils and plaques is associated with the pathologies of a range of neurological disorders and metabolic diseases, including Alzheimer’s disease (AD), Parkinson’s disease (PD) and type II diabetes mellitus (T2D). Human islet amyloid polypeptide (IAPP), specifically, contributes to glycemic control but also mediates the dysfunction of insulin-producing pancreatic β-cells in T2D. Furthermore, IAPP in circulation is capable of cross-seeding amyloid-beta and alpha-synuclein, associated with AD and PD respectively. Given no current anti-amyloid treatment is currently commercially available, fundamental understanding of amyloidosis within the complex cellular environment is required against amyloid diseases.
In this thesis, conditions to slow down the rapid fibrillization of IAPP to reduce or eliminate intermediate toxic aggregates have been identified in vitro. IAPP intermediate species were characterized and a novel ‘biannular’ morphology identified, with two distinct fibrillating populations then eliciting differential cytotoxicity to mature amyloids in primary cells in vitro. The behavior of fibrillating and fibrillar amyloid species in the presence of model proteins, lipids and ultrasmall lipid membranes was investigated, with regards to their effects on amyloid fibrillization, morphology and associated cytotoxicity in vitro, progressing then towards an in-depth study into the ‘protein corona’ formation of amyloid fibrils within complex biological media. Proteomic analysis identified amyloid-enriched proteins that are known to play significant roles in mediating cellular machinery and processing, potentially leading to pathological outcomes and therapeutic targets. Finally, a biocompatible star polymer (‘PHEA’) was synthesized to mimic the anti-amyloidosis properties of natural polyphenols and effectively rescue IAPP toxicity in mouse islets. Surprisingly, the relatively rigid and amphiphilic PHEA stars induced the formation of novel amyloid morphologies through promoting fibrillization, and accelerated amyloidogenesis to eliminate toxic intermediates in a fashion reminiscent of melanin production. This thesis outlines a logical progression towards the development of effective anti-amyloid strategies: whereby through first gaining insight into amyloidosis, this knowledge can be then applied to ameliorate amyloid pathologies.
Item Type: | Thesis (PhD) | ||||
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Subjects: | Q Science > QD Chemistry Q Science > QP Physiology |
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Library of Congress Subject Headings (LCSH): | Polypeptides, Amyloid, Proteins -- Metabolism -- Disorders | ||||
Official Date: | 2019 | ||||
Dates: |
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Institution: | University of Warwick | ||||
Theses Department: | Department of Chemistry | ||||
Thesis Type: | PhD | ||||
Publication Status: | Unpublished | ||||
Supervisor(s)/Advisor: | Ke, Pu Chun ; Wilson, Paul, 1984- ; Davis, Thomas P. (Thomas Paul), 1960- | ||||
Sponsors: | Australia. Depatment of Education, Skills and Employment ; Monash Institute of Pharmaceutical Sciences ; University of Warwick | ||||
Format of File: | |||||
Extent: | 228 leaves : illustrations (chiefly colour) | ||||
Language: | eng |
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