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. ? ? ?

Agency
National Institute of Health (NIH)
Institute
National Center for Research Resources (NCRR)
Type
Research Project (R01)
Project #
7R01RR002599-25
Application #
7754298
Study Section
National Center for Research Resources Initial Review Group (RIRG)
Program Officer
Moro, Manuel H
Project Start
1989-01-09
Project End
2011-06-30
Budget Start
2009-01-15
Budget End
2009-06-30
Support Year
25
Fiscal Year
2008
Total Cost
$144,551
Indirect Cost
Name
Sanford-Burnham Medical Research Institute
Department
Type
DUNS #
020520466
City
La Jolla
State
CA
Country
United States
Zip Code
92037
Kim, Teayoun; He, Lan; Johnson, Maria S et al. (2014) Carnitine Palmitoyltransferase 1b Deficiency Protects Mice from Diet-Induced Insulin Resistance. J Diabetes Metab 5:361
He, Lan; Kim, Teayoun; Long, Qinqiang et al. (2012) Carnitine palmitoyltransferase-1b deficiency aggravates pressure overload-induced cardiac hypertrophy caused by lipotoxicity. Circulation 126:1705-16
Luther, Rita J; Almodovar, Alvin J O; Fullerton, Russell et al. (2012) Acadl-SNP based genotyping assay for long-chain acyl-CoA dehydrogenase deficient mice. Mol Genet Metab 106:62-7
Nyman, Lara R; Tian, Liqun; Hamm, Doug A et al. (2011) Long term effects of high fat or high carbohydrate diets on glucose tolerance in mice with heterozygous carnitine palmitoyltransferase-1a (CPT-1a) deficiency: Diet influences on CPT1a deficient mice. Nutr Diabetes 1:e14
Spiekerkoetter, Ute; Wood, Philip A (2010) Mitochondrial fatty acid oxidation disorders: pathophysiological studies in mouse models. J Inherit Metab Dis 33:539-46
Zhang, Dongyan; Christianson, Jennifer; Liu, Zhen-Xiang et al. (2010) Resistance to high-fat diet-induced obesity and insulin resistance in mice with very long-chain acyl-CoA dehydrogenase deficiency. Cell Metab 11:402-11
Cox, Keith B; Liu, Jian; Tian, Liqun et al. (2009) Cardiac hypertrophy in mice with long-chain acyl-CoA dehydrogenase or very long-chain acyl-CoA dehydrogenase deficiency. Lab Invest 89:1348-54
Ji, Shaonin; You, Yun; Kerner, Janos et al. (2008) Homozygous carnitine palmitoyltransferase 1b (muscle isoform) deficiency is lethal in the mouse. Mol Genet Metab 93:314-22
Zhang, Dongyan; Liu, Zhen-Xiang; Choi, Cheol Soo et al. (2007) Mitochondrial dysfunction due to long-chain Acyl-CoA dehydrogenase deficiency causes hepatic steatosis and hepatic insulin resistance. Proc Natl Acad Sci U S A 104:17075-80
Sher, Roger B; Aoyama, Chieko; Huebsch, Kimberly A et al. (2006) A rostrocaudal muscular dystrophy caused by a defect in choline kinase beta, the first enzyme in phosphatidylcholine biosynthesis. J Biol Chem 281:4938-48

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