The overall goal of this program is to find or create and characterize new models of human inherited diseases. Such models are needed for improving greater understanding of pathogenesis and treatment of these burdensome, often fatal diseases. This program has successfully discovered animal models of human inherited diseases by systematically screening selected suspect animals. Recently developed molecular techniques and mouse embryonic stem (ES) cell technology now provide an additional approach for developing mouse models of any human inherited disease for which the gene has been cloned. These new techniques, along with metabolic screening methods, will be used to develop additional mouse models of human inherited disease. Emphasis will be given to developing additional models of straight chain fatty acid oxidation deficiency, an extension of previous work with the short chain acyl-CoA dehydrogenase (SCAD) deficient mouse.
Specific aims i nclude: (1) Develop, through site-directed mutagenesis/ES cell techniques, and characterize a mouse model of medium-chain acyl-CoA dehydrogenase (MCAD) deficiency. Mice with MCAD deficiency may be useful as a model for studies of the pathogenesis of sudden infant death syndrome (SIDS) and Reye-like syndrome (RLS). (2) Develop and characterize a mouse model of long-chain acyl-CoA dehydrogenase (LCAD) efficiency. Mice with this enzyme deficiency may be useful in investigating the prominent cardiomyopathy seen in LCAD deficient patients, as well as the pathology LCAD deficiency shares with other acyl-CoA dehydrogenase deficiencies. (3) Develop additional mouse models by crossing SCAD, MCAD and LCAD deficient mice to produce three models with double deficiency [(SCAD -/-, MCAD -/-, LCAD +/+), (SCAD -/-, MCAD +/+, LCAD -/-). or (SCAD +/+, MCAD -/-, LCAD -/-)] and a model with triple deficiency (SCAD -/-, MCAD -/-, LCAD -/-). These models, along with the models having single homozygous deficiencies above (SCAD, MCAD or LCAD), would permit investigation of fatty acid oxidation biology on a background of selected or total deficiency of straight-chain acyl-CoA dehydrogenation. From this group of seven unique models, one should find a few that will serve as excellent replicas of all human diseases of acyl-CoA dehydrogenase deficiencies. (4) Continue the successful program for metabolic screening of phenotypic-deviant mice and other animals to identify inherited metabolic diseases. New models will be characterized clinically, pathologically, biochemically and by molecular genetics, and made available to other investigators.
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