Among the inherited metabolic diseases, Gaucher disease (GD) is of particular importance since it is the most prevalent lysosomal storage disease. This disease is heterogeneous; all three clinically distinct subtypes result from the deficient activity (5-20% of normal) of acid Beta-glucosidase (Beta-Glc). The objective of the proposed research is to investigate the basic nature of this heterogeneity using enzymatic, cell biologic and molecular techniques. Employing newly developed affinity and HPLC techniques, Beta-Glc from normal and selected GD spleens will be purified to homogeneity for physicokinetic studies (kinetic isotope effects) and amino acid sequencing of the active site peptides. The structural (peptide maps), kinetic (enzyme modifiers) and immunologic (monoclonal antibody epitope maps; enzyme maturation) studies of monocyte/macrophage (M/M) and fibroblast Beta-GLc will be used to elucidate enzymatic defects characteristic of each GD subtype and to identify informative variants for molecular genetic studies. The toxic effects of substrate accumulation on M/M function (e.g., phagocytosis rates and interleukin 1 production) and maturation (using monoclonal antibodies to differentiation-specific surface antigens) will be assessed in substrate loaded normal and/or isolated and cultured GD M/M. Breeding colonies for the animal analogues of human GD will be established. The residual Beta-GLc activity, levels of toxic substrate accumulation and natural history of the murine and canine diseases will be characterized; these findings will provide the bases for evaluating future therapeutic endeavors in the animal analogues. Molecular techniques will be used to isolate full-length cDNA sequences for human Beta-G1c. These cDNA sequences will be used to investigate the normal gene structure and molecular defects in the human GD subtypes and variants as well as the animal analogues of GD by southern, northern and S1-nuclease analyses. These studies should provide insight into the molecular basis of the marked clinical heterogeneity in the GD subtypes. In addition, the animal models should provide the opportunity to evaluate transplantation and genetic strategies for the treatment of this and other inherited diseases.

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National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK)
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Biochemistry Study Section (BIO)
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Mount Sinai School of Medicine
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