Research Summary

Microscopic and spectroscopic investigation of dynamics and origin of structural polymorphism of amyloid fibrils of hIAPP: a target for rational design of amyloid inhibitors for diabetes therapy

The conversion of proteins from their soluble states into well ordered structures with a tubular morphology having a diameter of 15-20nm, classically referred to as amyloids, has been an interesting object of investigation for the past few decades. These structures are associated with many pathological conditions like Alzheimer’s disease (AD), systemic amyloidoses, taupathies, and diabetes mellitus type II.

Recent studies have shown that amyloids exhibit structural polymorphism resulting in aggregates with varied physio-chemical properties. However, little is known about their origin and physiological relevance in-vivo. This works aims at developing fluorescence based techniques to quantitatively determine the occurrence, properties (with respect to structural polymorphism) and physiological effects of polymorphic aggregation of human Islet Amyloid polypeptide (hIAPP) that is associated with beta cell mass degeneration in Diabetes mellitus type II.

Fluorescence lifetime changes of various solvate-chromic fluorescent dyes upon binding to amyloids would be primarily used to map fibril polymorphism of in-vitro generated and in-vivo produced hIAPP aggregates. Polymorphic assemblies would also be characterized by ss-NMR and electron microscopy to allow correlation of structural and morphological features to fluorescence properties. The knowledge gained would be used for design of peptide based anti-fibrillization molecules that would supplement diabetes therapy.