Amyloids in Type II Diabetes?

Submitted by James A. Hebda on Tuesday, 6/18/2013, at 2:26 PM

My thesis research was done in the lab of Andrew Miranker at Yale University in the Department of Molecular Biophysics and Biochemistry.

My thesis project explored the mechanism of Islet Amyloid Polypeptide (IAPP) amyloid formation.  I was particularly interested in determining the link between the alpha helical structure formed when IAPP binds anionic lipid membranes and the final beta sheet amyloid structure.

By collaborating with Ishu Saraogi, a graduate student from Andrew Hamilton's Lab, I was able to use novel alpha helical mimetic small molecules (IS compounds) to probe the mechanism of amyloid formation.  That research helped establish the importance of the helical region with IAPP, and that it may even be on pathway to beta sheet amyloid formation.  These conclusions were drawn from a synthesis of kinetic aggregation data and structural perturbations determined by 2D NMR.  The IS compounds accelerated amyloid fiber formation by binding to the helical region of IAPP, preventing helical structure formaion on membrane surfaces.  Additionally, the most effective of these compounds was also shown to reduce toxicity of IAPP to cultured INS-1 cells (a rat insulinoma cell line).  These data linked helical intermediates as both membrane toxic states and potential on pathway intermediates to amyloid assembly for IAPP.  This project resulted in several publications and continued research within the Miranker Lab.

Below is a copy of my Thesis.  It contains reformated versions of my published works, including a review on amyloid formation, focusing on the link to membrane bilayers.   It also has the results of some of my unpublished research that eventually led me to the Hamilton lab collaboration.

Although I am no longer working on Amyloids, I still feel close in topic.  Proteins don't know they are misfolding, they are only doing what they can with their sequence in the environment they find themselves.  My interest in protein folding has lead me to focus on the oligomerization and chaperone function of the important eye lens protein Alpha Cyrstallin.