Amyloid deposition occurs in more than twenty different human diseases. This project is concerned with amyloid formation by Islet Amyloid Polypeptide (IAPP), the endocrine hormone responsible for pancreatic islet amyloid in type 2 diabetes. Islet amyloid significantly contributes to the pathology of type 2 diabetes and is also a major problem in islet cell transplantation. Comparatively little is known about amyloid formation by IAPP despite its obvious importance and the mechanism underlying islet amyloid formation is not understood. The studies outlined here will;(1) determine the mechanism of amyloid formation by IAPP;(2) deduce the role of proIAPP processing intermediates in amyloid formation, a topic which has emerged as a critical issue in the last year (3) develop inhibitors of amyloid formation by IAPP and proIAPP and (4) test a general strategy for improving existing inhibitors of amyloid formation. The lessons learned will provide insight into strategies for the treatment and prevention of type 2 diabetes, and are expected to aid efforts to better control pathological amyloid formation in other diseases. An interdisciplinary combination of experimental biophysics, cell biology, and molecular dynamics simulations will be used to address these issues.
Three specific aims will be carried out. The first involves studies of the mechanism of amyloid formation by IAPP and is made up of four synergistic sub aims: A) The effects of modulating the conformational ensemble of monomeric IAPP on the kinetics of fibril formation will be determined;B) The hypothesis that a helical intermediate plays a critical role in amyloid formation by IAPP will be tested;C) The changes in secondary structure that occur during IAPP fibril formation will be defined with residue specific resolution;D) The role individual side chains play in amyloid formation by IAPP will be defined.
The second aim will define the role of pro-IAPP processing intermediates in amyloid formation.
The third aim will lead to the development of new inhibitors of amyloid formation by IAPP and test their ability to inhibit cell death. A general methodology for improving existing inhibitors will be tested as part of aim-3. PHS 398/2590 (Rev. 09/04, Reissued 4/2006) Page Continuation Format Page Principal Investigator/Program Director (Last, First, Middle): Raleigh, Daniel P.

Public Health Relevance

Amyloid formation refers to the pathological aggregation of proteins and occurs in more than twenty different human diseases including Alzheimer's disease and type-2 diabetes. This proposal is concerned with amyloid formation by Islet Amyloid Polypeptide (IAPP), the endocrine hormone responsible for pancreatic islet amyloid in type 2 diabetes. Islet amyloid significantly contributes to the pathology of type 2 diabetes The lessons learned from this work will provide insight into strategies for the treatment and prevention of type 2 diabetes, and will aid efforts to better control pathological amyloid formation in other diseases. PHS 398/2590 (Rev. 09/04, Reissued 4/2006) Page Continuation Format Page

Agency
National Institute of Health (NIH)
Institute
National Institute of General Medical Sciences (NIGMS)
Type
Research Project (R01)
Project #
3R01GM078114-03S1
Application #
8137422
Study Section
Macromolecular Structure and Function B Study Section (MSFB)
Program Officer
Wehrle, Janna P
Project Start
2008-07-01
Project End
2012-06-30
Budget Start
2010-07-01
Budget End
2011-06-30
Support Year
3
Fiscal Year
2010
Total Cost
$16,000
Indirect Cost
Name
State University New York Stony Brook
Department
Chemistry
Type
Schools of Arts and Sciences
DUNS #
804878247
City
Stony Brook
State
NY
Country
United States
Zip Code
11794
Abedini, Andisheh; Cao, Ping; Plesner, Annette et al. (2018) RAGE binds preamyloid IAPP intermediates and mediates pancreatic ? cell proteotoxicity. J Clin Invest 128:682-698
Ridgway, Zachary; Zhang, Xiaoxue; Wong, Amy G et al. (2018) Analysis of the Role of the Conserved Disulfide in Amyloid Formation by Human Islet Amyloid Polypeptide in Homogeneous and Heterogeneous Environments. Biochemistry 57:3065-3074
Serrano, Arnaldo L; Lomont, Justin P; Tu, Ling-Hsien et al. (2017) A Free Energy Barrier Caused by the Refolding of an Oligomeric Intermediate Controls the Lag Time of Amyloid Formation by hIAPP. J Am Chem Soc 139:16748-16758
Zhang, Xiaoxue; St Clair, Johnna R; London, Erwin et al. (2017) Islet Amyloid Polypeptide Membrane Interactions: Effects of Membrane Composition. Biochemistry 56:376-390
Raj, Shriya; Nazemidashtarjandi, Saeed; Kim, Jihyun et al. (2017) Changes in glucosylceramide structure affect virulence and membrane biophysical properties of Cryptococcus neoformans. Biochim Biophys Acta Biomembr 1859:2224-2233
Brar, Gurkirat S; Barrow, Breanne M; Watson, Matthew et al. (2017) Neprilysin Is Required for Angiotensin-(1-7)'s Ability to Enhance Insulin Secretion via Its Proteolytic Activity to Generate Angiotensin-(1-2). Diabetes 66:2201-2212
Young, Lydia M; Tu, Ling-Hsien; Raleigh, Daniel P et al. (2017) Understanding co-polymerization in amyloid formation by direct observation of mixed oligomers. Chem Sci 8:5030-5040
Akter, Rehana; Abedini, Andisheh; Ridgway, Zachary et al. (2017) Evolutionary Adaptation and Amyloid Formation: Does the Reduced Amyloidogenicity and Cytotoxicity of Ursine Amylin Contribute to the Metabolic Adaption of Bears and Polar Bears? Isr J Chem 57:750-761
Peran, Ivan; Watson, Matthew D; Bilsel, Osman et al. (2016) Selenomethionine, p-cyanophenylalanine pairs provide a convenient, sensitive, non-perturbing fluorescent probe of local helical structure. Chem Commun (Camb) 52:2055-8
Wong, Amy G; Wu, Chun; Hannaberry, Eleni et al. (2016) Analysis of the Amyloidogenic Potential of Pufferfish (Takifugu rubripes) Islet Amyloid Polypeptide Highlights the Limitations of Thioflavin-T Assays and the Difficulties in Defining Amyloidogenicity. Biochemistry 55:510-8

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