Mitochondrial fatty acid beta-oxidation (FAO) is required for normal life processes in mammals. Deficiencies of enzymes that have a role in FAO have been associated with a family of poorly understood diseases. These diseases range in severity from subclinical manifestations to life threatening disease such as acute Reye Syndrome-like illness, cardiomyopathy, and sudden death. Many of the experiments proposed are crucial to development of better disease prevention and treatment approaches to these inherited diseases, as well as, understanding basic biology of lipid metabolism.
The specific aims of the current proposal are to: (1) Complete the development and characterization of medium- chain acyl-CoA dehydrogenase (MCAD) and carnitine palmitoyltransferase (CPT-1 and 2) deficient mouse models currently in progress, and produce congenic lines of the most useful models. (2) Determine the role and importance of doubly heterozygous FAO enzyme deficiency state in disease pathogenesis. (3) Investigate the effectiveness of metabolic therapy strategies designed to by-pass FAO enzyme deficiency and provide energy sources not requiring enzyme the deficient step. (4) Investigate the mechanisms responsible for embryo loss in long-chain acyl-CoA dehydrogenase (LCAD) deficient mice and possible therapeutic strategies for correction of this phenotype. There are three reproducible disease characteristics of cold intolerance, cardiac hypertrophy, and embryonic loss for experimental evaluation in these models. Therefore, these studies address some of the crucial issues in the field. The mouse models developed and characterized in these studies will create unique opportunities to investigate basic disease mechanisms that are impossible to study in children with inborn errors of fatty acid metabolism. There have been many requests for these mutant mice or materials derived from these models, therefore, these models are contributing significantly to ongoing research that is relevant to several NIH institutes including NIDDK, NICHD, and NHLB.
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