Dissertation/Thesis Abstract

Mechanistic and Structural Insight into Amyloid Formation by Islet Amyloid Polypeptide: Implications for Monitoring the Amylome
by Wong, Amy Gar-lai, Ph.D., State University of New York at Stony Brook, 2016, 230; 10252614
Abstract (Summary)

Amyloid fibrils are insoluble peptide or protein aggregates that are fibrous, predominantly β-sheet, and highly ordered. Amyloid formation plays an important role in an array of human diseases including Alzheimer’s, Parkinson’s, and Huntington’s disease. The proteins that form amyloid vary greatly in native structure and function however, the resultant amyloid plaques formed when these proteins misfold share many structural features. The work herein describes the recent research on islet amyloid polypeptide (IAPP, or amylin), a neuroendocrine hormone that is co-secreted with insulin and has been observed to form amyloid plaques in the pancreas, a process that has been shown to be toxic to β-cells and a ubiquitous feature in patients with type-2 diabetes. The structure and mechanism of IAPP is currently not known. Additionally, current methods of monitoring the formation of amyloid by IAPP have inherent weaknesses that can lead to misleading results. A clearer picture of the mechanism of amyloid formation by IAPP, the structure of the mature fibril, as well as the development of more robust methods of monitoring amyloid formation in real time could lead to improved therapeutics and alluring candidates for xenobiotic transplantation.

In this dissertation, the role of helical intermediates in amyloid formation was explored by performing several replacements at position-17 in the IAPP sequence. The veracity of several amyloid prediction programs was also investigated and the ability of pufferfish IAPP to form amyloid was investigated which subsequently, revealed pitfalls in the commonly used thioflavin-T fluorescence assay. Several potential dyes were explored in order to provide alternative means of monitoring amyloid formation by IAPP in real time. In addition, baboon IAPP was examined, specifically it’s toxicity to INS-1 β-cells and the distribution of oligomers populated during the lag phase. Finally, the role of the disulfide bond between Cys-2 and Cys-7 was explored by examining truncated variants of IAPP and reduced models of the peptide.

Indexing (document details)
Advisor: Raleigh, Daniel P.
Commitee: Boon, Elizabeth, Simmerling, Carlos, Stockman, Brian J.
School: State University of New York at Stony Brook
Department: Chemistry
School Location: United States -- New York
Source: DAI-B 78/07(E), Dissertation Abstracts International
Source Type: DISSERTATION
Subjects: Chemistry
Keywords: Amylin, Amyloid, Diabetes, Islet amyloid polypeptide, Thioflavin-T
Publication Number: 10252614
ISBN: 9781369627312
Copyright © 2019 ProQuest LLC. All rights reserved. Terms and Conditions Privacy Policy Cookie Policy
ProQuest