1. The metabolic defect in patients with Types C and D Niemann- Pick disease has been shown to be due to abnormal Intracellular cholesterol homeostasis. The molecular lesion in these disorders results in: (1) failure to down-regulate LDL receptors on cell membranes; (2) lack of down-regulation of HMGCoA reductase, a key enzyme in cholesterol biosynthesis; and (3) inability to up- regulate acyl cholesterol acyl CoA transferase, the enzyme that catalyzes the esterification of intracellular cholesterol. Tests for the diagnosis of Types C and D Niemann-Pick disease and the identification of heterozygotes, and the prenatal diagnosis of these conditions. 2. Other work has centered on the synthesis and use of non- metabolizable analogs of glucocerebroside to examine the pathogenesis of Gaucher's disease and to develop a rodent model of the human disorders. An analog of glucocerebroside has been synthesized that appears to be useful for the selection of mutagenized cells that lack glucocerebrosidase, the enzyme lacking in Gaucher's disease. These cells will be used to construct a transgenic murine analog of Gaucher's disease.
