Inherited diseases of mitochondrial fatty acid oxidation (FAO) remain a challenge for diagnosis, prognosis, and therapy because there often is a poor genotype-phenotype correlation. Inborn errors of metabolism are multisystem disorders and complex traits affected by genomic and environmental influences.
The specific aims of this competing continuation project include: (1) Develop and characterize new mouse models for carnitine palmitoyltransferase-1b (muscle isoform) deficiency. (2) Complete the characterization of a new mouse model for fatty acid synthase deficiency. (3) Develop new double heterozygous deficient mouse models that allow further investigation of the role of """"""""synergistic heterozygosity"""""""" in the development of acute metabolic crisis and chronic disease such as cardiac hypertrophy. This includes investigation of the quantitative effects of the combination of heterozygous enzyme deficiencies in different parts of the FAO pathway (carnitine palmitoyltransferase-1a (liver isoform), long-chain acyl-CoA dehydrogenase [LCAD], mitochondrial trifunctional protein [MTP] and the isolated component of MTP, long-chain 3-hydroxy-acyl-CoA dehydrogenase [LCHAD] deficiency in combination with the heterozygous deficiency of a key transcription factor peroxisomal proliferator activated receptor-a that regulates expression of many of the enzyme genes in the FAO pathway. (4) Investigate the role of genetic background and dietary macronutrient (fat, carbohydrates) influences on development of acute disease in homozygous LCAD deficient mice. (5) Maintain colonies of the mutant mouse lines produced in this project and submit each to a mutant mouse resource. Collaborative studies to characterize these models in regard to development of insulin resistance and type 2 diabetes mellitus will continue. Therefore, this project will continue to develop and investigate mouse models with inherited deficiencies in the ability to """"""""burn fat."""""""" These are potentially fatal diseases affecting mostly children who cannot withstand fasting, exercise and common childhood infectious diseases. This project will begin to explore, beyond a single enzyme deficiency, the complex interaction between genetics and environmental challenges to these patients for improvement in their diagnosis, prognosis and treatment. The results of these studies could have wide ranging impact on understanding the underlying bases of many other inherited diseases.
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