Project 2
Martha Skinner, MD |
TISSUE RESPONSE TO AMYLOIDOGENIC LIGHT CHAINS
Project Leader: Martha Skinner, M.D., Professor of Medicine, Director, Amyloid Treatment & Research Program
The overall goal of our Program Project Grant is to clarify mechanisms of light chain (LC) fibril formation and tissue toxicity, and to develop novel diagnostic and therapeutic approaches for AL amyloidosis. We hypothesize that amyloidogenic LCs initiate formation of oligomeric aggregates through complex mechanisms linking unfolding to aggreggation, enhanced by proteoglycan and/or glycosaminoglycan (GAG) association. The process leading to amyloid fibrils may be enhanced by tissue-specific molecules. A toxic effect of LCs in organ systems is hypothesized to be caused by alterations in cellular signaling induced by the prefibrillar aggregates as well as tissue amyloid deposits. We have purified, sequenced, and identified post-translational modifications of amyloidogenic LCs obtained from patient samples. Out of 200 samples collected, more than 60 have been purified with full or partial sequence data indicating extensive structural diversity. Kappa 1 sequences have been analyzed in detail, and studies using circular dichroism (CD) and light scattering to analyze the linkage between protein unfolding, misfolding, and aggregation are ongoing. We are studying the role of GAGs, and other tissue-specific accessory molecules that have been identified by proteomic studies. We are examining how LCs alter the ability of endothelial cell-cardiomyocyte paracrine signals to regulate cardiomyocyte structure and function. We are beginning to screen a library of GAG mimetics as potential therapeutic agents to prevent LC aggregation, toxicity, and formation of amyloid fibril deposits.
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