EXCEED THE SPACE PROVIDED. Until recently, amyloidosis was considered an obscure disease. The role of amyloid in adult-onset diabetes, and its potential contribution to Alzheimer's disease are among the factors that have stimulated much heightened ; attention to the molecular bas.es of these disorders. In addition,the physicochemical properties that cause some proteins to form amyloids are.relevant to other protein aggregation, or conformational,diseases ranging from cataracts to Parkinson's disease. While most antibody light chains show no tendency to aggregate or cause i disease, some form amyloid fibrils and others are involved in nonfibrillardeposition disease. Our work has (1) ; shown a well-defined stability threshold that separates fibrillogenic and nonfibrillogeniclight chains when tested in vitro; (2) found it possible to identify over 80% of known human amyloidogenic K! light chains by the presence of at least one mutationfrom a set of four molecular risk factors. (We believe this to be the first evidence that amyloidogenic light chains can be identifiedon the basis of primary structure.); and (3) found that certain sequence-specific peptides block fibril formation in vitro, suggesting lead compounds for eventual drugs | for clinical management of light chain amyloidosis. This proposed project will attempt to provide amolecular mechanism for light chain fibril formation.
The first Aim tests a proposed conformational change that initiates ; fibrillogenesis by using inhibitory peptides, mutational analysis and crystallography.
The second Aim extends the inferences from our highly focused study of the K4subgroup to Kl, XI, and X3subgroups by generating selected mutants that will confirm the existence of fibril stability thresholds and determining subgroup specific ; variations in this threshold. Additionally, the surfaces of interaction during fibril assembly will be mapped. The goal of improved patient care will be addressed by exploring the effectiveness of peptides as a general strategyfor development of drugs for arnyloidoses.
A third aim i s directed toward the development of a transgenic mouse model for light chain amyloidosis. Such a model will provide in vivo validationfor the significance: of the in vitro properties introduced by mutations to the development of amyloidosis. PERFORMANCE SITE ========================================Section End===========================================
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