Type
Text
Type
Dissertation
Advisor
Raleigh, Daniel P | Tonge, Peter J | Carrico, Isaac | Baum, Jean.
Date
2012-05-01
Keywords
Amyloid, Islet Amyloid Polypeptide | Chemistry--Biophysics
Department
Department of Chemistry
Language
en_US
Source
This work is sponsored by the Stony Brook University Graduate School in compliance with the requirements for completion of degree.
Identifier
http://hdl.handle.net/11401/71339
Publisher
The Graduate School, Stony Brook University: Stony Brook, NY.
Format
application/pdf
Abstract
Amyloid deposition has been implicated to play a role in the pathology of over 40 human diseases including Alzheimer's, Parkinson's, type 2 diabetes and systemic amyloidosis, to name a few. All amyloid fibrils are characterized by a cross &beta-pleated sheet structure with interstrand hydrogen bonds running parallel to the long axis of the fibril. Islet amyloid polypeptide (IAPP) is a 37-residue peptide hormone that is the major proteinaceous component of pancreatic islet amyloid deposition that develops during type 2 diabetes. These deposits have been shown to play a role in the decrease of islet mass and &beta-cell apoptosis, which are typical pathologies developed during type 2 diabetes. The aggregation process of how IAPP goes from an unstructured monomer to an ordered peptide aggregate with significant &beta-sheet secondary structure is highly complex and involves a number of transient species that are highly dynamic and metastable. This research provides insights into the biophysical mechanisms and environmental components that can enhance amyloid assembly by IAPP using chemical, biophysical and kinetic methods. My work included the development of a new method to synthesize IAPP via microwave solid-phase peptide synthesis; the examination of the role of aromatic amino acids in IAPP via a triple mutant in which the three aromatic amino acids were substituted with leucines; probing the nature lag phase species populated during amyloid formation via the unnatural fluorescent amino acid, p-cyanophenylalanine; and the study of the effects of ionic strength and ion composition on amyloid formation by IAPP. These studies aim to provide a better understanding of the intrinsic factors inherent to IAPP, as well as extrinsic environmental factors, that can decrease the stability of monomeric IAPP and induce amyloid formation. | 205 pages
Recommended Citation
Marek, Peter James, "Biophysical Insights into Amyloid Formation by Islet Amyloid Polypeptide" (2012). Stony Brook Theses and Dissertations Collection, 2006-2020 (closed to submissions). 545.
https://commons.library.stonybrook.edu/stony-brook-theses-and-dissertations-collection/545