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. ? ?

Agency
National Institute of Health (NIH)
Institute
National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK)
Type
Research Project (R01)
Project #
5R01DK055675-07
Application #
6886712
Study Section
Molecular and Cellular Biophysics Study Section (BBCA)
Program Officer
Rasooly, Rebekah S
Project Start
1999-05-01
Project End
2007-04-30
Budget Start
2005-05-01
Budget End
2006-04-30
Support Year
7
Fiscal Year
2005
Total Cost
$318,613
Indirect Cost
Name
University of California Santa Cruz
Department
Chemistry
Type
Schools of Arts and Sciences
DUNS #
125084723
City
Santa Cruz
State
CA
Country
United States
Zip Code
95064
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Qin, Zhijie; Hu, Dongmei; Zhu, Min et al. (2007) Structural characterization of the partially folded intermediates of an immunoglobulin light chain leading to amyloid fibrillation and amorphous aggregation. Biochemistry 46:3521-31
Khurana, Ritu; Coleman, Chris; Ionescu-Zanetti, Cristian et al. (2005) Mechanism of thioflavin T binding to amyloid fibrils. J Struct Biol 151:229-38
Uversky, Vladimir N; Fink, Anthony L (2004) Conformational constraints for amyloid fibrillation: the importance of being unfolded. Biochim Biophys Acta 1698:131-53
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Souillac, Pierre O; Uversky, Vladimir N; Fink, Anthony L (2003) Structural transformations of oligomeric intermediates in the fibrillation of the immunoglobulin light chain LEN. Biochemistry 42:8094-104
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