# Biophysical Studies of Amyloid Formation by Polypeptide Hormones

> **NIH NIH R01** · STATE UNIVERSITY NEW YORK STONY BROOK · 2024 · $351,160

## Abstract

PROJECT SUMMARY
This application describes an interdisciplinary program designed to study amyloid formation by human islet
amyloid polypeptide (hIAPP, also known as amylin), the causative agent of pancreatic islet amyloidosis-induced
beta-cell toxicity in diabetes. Amyloid formation by hIAPP is a well-established pathological factor contributing to
the development of type 2 diabetes, a debilitating disease that has reached epidemic proportions in the United
States. Islet amyloidosis is also a major contributor to islet cell transplantation failure. Aggregation of hIAPP has
recently been implicated in islet beta-cell deficiency in type 1 diabetes, and in the downstream cardiovascular
complications of diabetes. hIAPP is normally secreted as a soluble polypeptide hormone together with insulin from
the pancreatic beta-cells and plays an adaptive role in glucose metabolism, including the regulation of the action
of insulin and other pancreatic metabolic hormones. However, in metabolic disease, hIAPP aggregates into
cytotoxic conformations that assemble into amyloid fibrils that deposit as plaques in the islets. The process of
islet amyloid formation is toxic to beta-cells and plays an important role in disease progression. Wild type hIAPP
is responsible for islet amyloidosis in the majority of individuals, but an S20G mutation is linked to an increased
risk of diabetes. Soluble analogs of hIAPP are of interest as adjuncts to insulin therapy for the treatment of
diabetes, particularly for type 1 diabetes, where the rapid loss of beta-cells results in dependence on hormone
replacement therapy. Soluble hIAPP analogs are also of interest for the potential treatment of obesity. The
planned studies address fundamental issues in amyloid formation, and will offer important insight into strategies
for the treatment of type 1 and type 2 diabetes. We will apply an interdisciplinary combination of protein
biophysics, biochemistry, and islet cell biology to address three key issues in the field: 1) defining the
determinates of hIAPP amyloid formation and toxicity, including the role of specific amino acid sidechain
interactions; 2) elucidating the reasons for the aggressive aggregation and heightened toxicity of the S20G
mutant of hIAPP; and 3) the rational development and rigorous testing of next generation soluble analogs of
hIAPP. The studies will define the molecular features impacting hIAPP amyloid formation and islet beta-cell toxicity.
They will identify general principles that will be broadly applicable to other protein aggregation diseases, and to
mechanistic studies of amyloid formation.

## Key facts

- **NIH application ID:** 10877020
- **Project number:** 5R01GM078114-16
- **Recipient organization:** STATE UNIVERSITY NEW YORK STONY BROOK
- **Principal Investigator:** DANIEL P RALEIGH
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2024
- **Award amount:** $351,160
- **Award type:** 5
- **Project period:** 2008-07-01 → 2026-06-30

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10877020

## Citation

> US National Institutes of Health, RePORTER application 10877020, Biophysical Studies of Amyloid Formation by Polypeptide Hormones (5R01GM078114-16). Retrieved via AI Analytics 2026-05-24 from https://api.ai-analytics.org/grant/nih/10877020. Licensed CC0.

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