| dc.identifier.uri | http://hdl.handle.net/11401/77063 | |
| dc.description.sponsorship | This work is sponsored by the Stony Brook University Graduate School in compliance with the requirements for completion of degree. | en_US |
| dc.format | Monograph | |
| dc.format.medium | Electronic Resource | en_US |
| dc.language.iso | en_US | |
| dc.publisher | The Graduate School, Stony Brook University: Stony Brook, NY. | |
| dc.type | Dissertation | |
| dcterms.abstract | 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. | |
| dcterms.abstract | 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. | |
| dcterms.available | 2017-09-20T16:51:49Z | |
| dcterms.contributor | Simmerling, Carlos | en_US |
| dcterms.contributor | Raleigh, Daniel P | en_US |
| dcterms.contributor | Boon, Elizabeth | en_US |
| dcterms.contributor | Stockman, Brian J. | en_US |
| dcterms.creator | Wong, Amy | |
| dcterms.dateAccepted | 2017-09-20T16:51:49Z | |
| dcterms.dateSubmitted | 2017-09-20T16:51:49Z | |
| dcterms.description | Department of Chemistry | en_US |
| dcterms.extent | 230 pg. | en_US |
| dcterms.format | Application/PDF | en_US |
| dcterms.format | Monograph | |
| dcterms.identifier | http://hdl.handle.net/11401/77063 | |
| dcterms.issued | 2016-12-01 | |
| dcterms.language | en_US | |
| dcterms.provenance | Made available in DSpace on 2017-09-20T16:51:49Z (GMT). No. of bitstreams: 1
Wong_grad.sunysb_0771E_13154.pdf: 5668327 bytes, checksum: 63680f1a2c4b8a47559c5497310027c0 (MD5)
Previous issue date: 1 | en |
| dcterms.publisher | The Graduate School, Stony Brook University: Stony Brook, NY. | |
| dcterms.subject | Chemistry | |
| dcterms.subject | Amylin, Amyloid, Diabetes, Islet Amyloid Polypeptide, Thioflavin-T | |
| dcterms.title | Mechanistic and Structural Insight into Amyloid Formation by Islet Amyloid Polypeptide: Implications for Monitoring the Amylome | |
| dcterms.type | Dissertation | |
