Mounting evidence suggests that the aggregation of islet amyloid polypeptide (IAPP) is associated with ?-cell death in type-2 diabetes (T2D). IAPP, a 37-residue peptide hormone secreted by ?-cells, readily forms amyloid fibrils in vitro at M concentrations. The aggregates of IAPP, either insoluble amyloid fibrils or soluble oligomers, are found toxic to ?-cells. Inhibition of IAPP aggregation is an attractive therapeutic strategy to prevent ?-cell death and stop the progression of diabetic conditions in T2D. Interestingly, no apparent IAPP aggregates are observed in healthy individuals where IAPP is stored in ?-cell granules at mM concentrations. Therefore, physiological conditions of ?-cell granules natively inhibit amyloid aggregation of IAPP. Disruption of the inhibitive environment of ?-cell granules may lead to the accumulation of toxic IAPP aggregates, causing ?- cell death and the diabetic condition of insulin deficiency in T2D. Molecular mechanisms of the native inhibition of hIAPP aggregation are largely unknown, which limit the design of novel therapeutic approaches that either promote or mimic the native inhibition. In addition, several naturally-occurring small-molecule polyphenols displayed inhibitory effects on hIAPP aggregation. However, many of these small molecules have low water solubility, which limits their bioavailability and biodistribution. Knowledge of the mechanism of action of these polyphenols may help design de novo small-molecule drugs that can inhibit hIAPP aggregation with higher efficacy and solubility. Further more, our preliminary studies combining in silico modeling with in vitro and ex vivo characterization indicated that the generation-3 polyamidoamin (PAMAM) dendrimer, a polymeric nanoparticle commonly used for drug delivery, could also inhibit hIAPP aggregation. Our results pointed to a promising nanomedicinal approach for both efficient loading of ant-amyloid drug and inhibitory effect on hIAPP aggregation. In this MIRA application, the PI proposes the following three projects to uncover various inhibition mechanisms of hIAPP aggregation: 1) to delineate the inhibitive mechanism of the environmental elements of granules on IAPP aggregation; 2) to uncover the inhibition mechanism of hIAPP aggregation by small-molecule polyphenols; and 3) to explore dendritic nanoparticles with increased small-molecule loading and inhibitive effects on hIAPP aggregation. The PI lab will combine computational modeling with experimental characterization and validation. Computational modeling can help bridge the gaps of time and length scales between experimental observations and the underlying molecular systems, providing not only molecular insight to experimental observations but also offering experimentally-testable hypotheses. Such a combined computational and experimental approach can improve research efficiency and shorten discovery cycle. The outcome of the proposed studies will help design therapeutic strategies to either promote or mimic the native inhibition (Project 1), novel small-molecule inhibitors with enhanced anti-amyloid efficacy (Project 2), and engineered NPs with both high drug delivery and enhanced anti-aggregation properties (Project 3).

Public Health Relevance

Aggregation of human islet amyloid polypeptide (hIAPP) is associated with type-2 diabetes (T2D). We propose to delineate the inhibition mechanism of hIAPP aggregation under the cellular environment of pancreatic beta- cells, by naturally-occurring small molecules, and by engineered nanoparticles. Outcome of the proposed research will help better understand the disease mechanism of T2D, design therapeutics that promote or mimic the native-like inhibition, and search for anti-amyloid inhibitors and nanomedicines against hIAPP aggregation.

Agency
National Institute of Health (NIH)
Institute
National Institute of General Medical Sciences (NIGMS)
Type
Unknown (R35)
Project #
5R35GM119691-02
Application #
9340249
Study Section
Special Emphasis Panel (ZRG1-CB-B (50)R)
Program Officer
Wehrle, Janna P
Project Start
2016-09-01
Project End
2021-05-31
Budget Start
2017-06-01
Budget End
2018-05-31
Support Year
2
Fiscal Year
2017
Total Cost
$361,951
Indirect Cost
$111,951
Name
Clemson University
Department
Physics
Type
Schools of Arts and Sciences
DUNS #
042629816
City
Clemson
State
SC
Country
United States
Zip Code
29634
Sun, Yunxiang; Ge, Xinwei; Xing, Yanting et al. (2018) ?-barrel Oligomers as Common Intermediates of Peptides Self-Assembling into Cross-? Aggregates. Sci Rep 8:10353
Kakinen, Aleksandr; Adamcik, Jozef; Wang, Bo et al. (2018) Nanoscale inhibition of polymorphic and ambidextrous IAPP amyloid aggregation with small molecules. Nano Res 11:3636-3647
Ge, Xinwei; Sun, Yunxiang; Ding, Feng (2018) Structures and dynamics of ?-barrel oligomer intermediates of amyloid-beta16-22 aggregation. Biochim Biophys Acta Biomembr 1860:1687-1697
Pilkington, Emily H; Gustafsson, Ove J R; Xing, Yanting et al. (2018) Profiling the Serum Protein Corona of Fibrillar Human Islet Amyloid Polypeptide. ACS Nano :
Wang, Miaoyi; Sun, Yunxiang; Cao, Xueying et al. (2018) Graphene quantum dots against human IAPP aggregation and toxicity in vivo. Nanoscale 10:19995-20006
Ge, Xinwei; Yang, Ye; Sun, Yunxiang et al. (2018) Islet Amyloid Polypeptide Promotes Amyloid-Beta Aggregation by Binding-Induced Helix-Unfolding of the Amyloidogenic Core. ACS Chem Neurosci 9:967-975
Faridi, Ava; Sun, Yunxiang; Okazaki, Yutaka et al. (2018) Mitigating Human IAPP Amyloidogenesis In Vivo with Chiral Silica Nanoribbons. Small 14:e1802825
Yanez Orozco, Inna S; Mindlin, Frank A; Ma, Junyan et al. (2018) Identifying weak interdomain interactions that stabilize the supertertiary structure of the N-terminal tandem PDZ domains of PSD-95. Nat Commun 9:3724
Yang, Jiang; Wang, Bo; You, Youngsang et al. (2017) Probing the modulated formation of gold nanoparticles-beta-lactoglobulin corona complexes and their applications. Nanoscale 9:17758-17769
Sun, Yunxiang; Wang, Bo; Ge, Xinwei et al. (2017) Distinct oligomerization and fibrillization dynamics of amyloid core sequences of amyloid-beta and islet amyloid polypeptide. Phys Chem Chem Phys 19:28414-28423

Showing the most recent 10 out of 19 publications