Our long-term goal is to understand the detailed molecular mechanisms of protein deposition diseases and the factors that trigger amyloid fibril formation. Protein deposition diseases are of increasing prevalence, due to the aging of the population. Understanding the mechanisms of deposition will facilitate the rational design of clinical therapies. In this proposal, we focus on a constellation of diseases known as light chain deposition diseases, in particular on AL or light chain amytoidosis, sometimes also known as primary amyloidosis, which is the most common systemic amyloidosis. These diseases involve the deposition of the variable domain of the immunoglobulin light chain, VL. We will continue our studies on the properties of a pair of closely related VLs, one amyloidogenic (SMA), the other benign (LEN).
Aim 1 is to elucidate the detailed molecular mechanism of light chain aggregation, especially with respect to characterizing intermediates and the mechanisms by which various factors accelerate or inhibit light chain fibrillation.
Aim 2 is to investigate the role of surfaces, especially membranes, in light chain fibrillation. Based on preliminary results, we hypothesize that surfaces play a very important role in the initiation of fibrillation.
Aim 3 is to investigate the rote of oxidation and oxidative stress on the fibrillation of light chain variable domains. Oxidative stress is thought to be an important factor in the etiology of many protein deposition diseases.
Aim 4 is to find inhibitors of light chain aggregation and fibril formation. We hypothesize that appropriate peptides will act as inhibitors of aggregation through several possible mechanisms. We will screen both a combinatorial peptide library and peptide fragments from light chains as well as some low MW compounds for potential inhibitors of VL fibrillation. ? ?
