Types A & B Niemann-Pick Disease (NPD) are lipid storage disorders resulting from the deficient activity of the lysosomal hydrolase, acid sphingomyelinase (ASM). Type A NPD is a severe neuro-degenerative disorder, which leads to death in early childhood, while patients with Type B NPD have little or no neurological abnormalities and often survive into adulthood. The overall goals of this research are to investigate the underlying causes of the distinct neurological & non-neurological forms of NPD, including the role of ASM in ceramide-mediated cell signaling & disease pathogenesis, and to develop effective treatments for these disorders. Previously, our laboratory: 1) Isolated the full-length cDNAs & genes encoding human & murine ASM, 2) Identified the first ASM mutations causing NPD & developed the first NPD molecular diagnostic program, 3) Constructed a knock-out mouse model for this disorder, 4) Stably over-expressed, purified & characterized recombinant human ASM from CHO cells, 5) Evaluated enzyme replacement, bone marrow transplantation & hematopoietic stem cell gene therapy in the NPD mouse model, and 6) Characterized ceramide-mediated signal transduction in the NPD mouse. In the upcoming funding period we are proposing four specific aims: 1) Investigate the pulmonary disease in NPD mice & develop lung-specific therapies for Type B NPD, 2) Investigate the neurological disease in NPD mice & develop CNS-specific therapies for Type A NPD, 3) Investigate the reproductive biology of NPD mice, including the development of approaches for the selection of normal vs. NPD gametes and preimplantation embryos, and 4) Continue to conduct world-wide ASM mutation analysis & structure/function studies. We believe that this research will provide fundamental insights into the underlying biology of NPD & ASM, and lead to the development of effective treatments for these disorders and/or methods to prevent or minimize NPD births.
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