Program Project Grant
Immunoglobulin Light Chain Fibrillogenesis
Supported by the National Heart, Lung, and Blood Institute of the
National Institutes of Health (P01 HL68705)
Principal Investigator
David Seldin, MD, PhD
Professor of Medicine and Microbiology
Boston University Medical Center
This project is designed to elucidate the pathophysiology of the rare and understudied disease AL amyloidosis and to develop novel therapeutics. AL or "primary" amyloidosis is a clonal plasma cell dyscrasia, occuring alone or in combination with multiple myeloma or other B lymphoproliferative disorders. In AL amyloidosis, clonal immunoglobulin light chains (LC) polymerize and produce potentially fatal organ damage.
The determinants of disease and the mechanisms of tissue toxicity are not well understood. To make inroads into these questions, in the initial funding period of this grant, we made significant progress towards the Program's goals: we developed a database "ALBase" of more than 200 amyloidogenic LC from Boston Medical Center patients (now seen in the new J. Joseph Moakley Building), analyzed their biochemical and clinical features, expressed LC in vitro, and developed in vivo animal models (Project 1); we analyzed post-translational modifications of LC by mass spectrometry and 2D gel electrophoresis, documented acute toxicity, oxidative stress, and uptake of LC in cell and organ culture models, and demonstrated co-regulation of GAGs and LC (Project 2); and, we developed techniques for antigen presentation using CD40L-activated B cells, identified and validated suitable antigen candidates from plasma cells using algorithms to predict interactions with Class I HLA molecules, and developed effective adjuvants and vaccination protocols in mouse models (Project 3). These projects are supported by state-of-the-art cores: Protein Biochemistry and Tissue Analysis (Core A), Mass Spectrometry (Core B), and Administrative and Data Management (Core C).
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