Type
Text
Type
Dissertation
Advisor
Wang, Jin | Raleigh, Daniel P | Lauher, Joseph | Seeliger, Markus.
Date
2014-12-01
Keywords
amylin, amyloid, IAPP | Biochemistry
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/11401/77162
Publisher
The Graduate School, Stony Brook University: Stony Brook, NY.
Format
application/pdf
Abstract
Amyloid formation, the aggregation of normally soluble proteins or polypeptides into highly ordered beta-sheet structures, is a characteristic feature of many human diseases including Alzheimer's disease, Parkinson's disease and type 2 diabetes. I centered my research on islet amyloid polypeptide (IAPP), a neuroendocrine hormone that forms fibrillar amyloid deposits in the extracellular space of the pancreatic islets of Langerhans in type 2 diabetes. Although whether IAPP amyloid formation is a cause or consequence of the disease is controversial, the aggregation process has been shown to induce beta-cell apoptosis and reduce beta-cell mass, which is a hallmark feature of type 2 diabetes. The mechanism of islet amyloid formation is not understood yet. Moreover, although there are some reported IAPP amyloid inhibitors, either peptide-based or small-molecule, lack of the clear modes of their actions impedes further development and their clinical use. A better understanding of the amyloidsis and inhibition mechanism could help explain the pathogenesis of type 2 diabetes and could lead to improved treatment for the disease. My work included a study of the effects of glycosaminoglycans, the main component of extracellular matrix which was believed to play a role in in vivo islet amyloid initiation and progression, on in vitro amyloid formation and inhibition; an investigation of the possible role of impaired proIAPP processing in islet amyloid formation; a rational design of several IAPP analogs with better solubility at neutral pH than a FDA approved drug, promising better adjunct drug candidates to insulin therapy for diabetes patients; a study to elucidate the factors which lead to optimum peptide based inhibitors of IAPP amyloid formation by examining the ability of a set of designed polypeptide analogs of IAPP; a critical examination of the inhibition of IAPP amyloid formation by inositol. | 216 pages
Recommended Citation
Wang, Hui, "Biophysical Insights into the Initiation and Inhibition of Amyloid Formation by Islet Amyloid Polypeptide" (2014). Stony Brook Theses and Dissertations Collection, 2006-2020 (closed to submissions). 2998.
https://commons.library.stonybrook.edu/stony-brook-theses-and-dissertations-collection/2998