AMP deaminase and the purine nucleotide cycle of which it is one component are important for energy metabolism in may tissues. The role of this cycle in energy metabolism has been best studied in skeletal muscle where the activities of these enzymes are particularly high, tissue-specific isoforms are found, and flux through the cycle increases dramatically with exercise. The clinical relevance of this cycle in skeletal muscle is highlighted by the myopathy which develops in patients with inherited deficiencies of nucleotide cycle enzymes. AMP deaminase deficiency, the most common defect in this cycle, is associated with an exercise-related myopathy. The purpose of these studies is to understand the regulation of AMP deaminase expression in normal and pathological conditions. AMP deaminase exists in multiple isoforms, some of which are tissue- specific. One set of projects is designed to use isoform specific anti-sera and nucleic acid probes to study developmental and tissue-specific control of isoform expression in animal models and a tissue culture model of myocyte differentiation. Another set of experiments is designed to assess the function of different domains of AMP deaminase through the use of in vivo and in vitro expression vectors with the goal of localizing isoform-specific properties to different domains. A third set of projects is designed to determine the molecular bases of inherited and acquired deficiencies of AMP deaminase through the study of patients using isoform-specific and nucleic acid probes. Results of these studies have direct relevance to understanding the control of AMP deaminase and the purine nucleotide cycle in normal conditions and to understanding the pathogenesis of AMP deaminase deficiency. The results may have broader significance by providing additional insight to processes which control myocyte differentiation.

Agency
National Institute of Health (NIH)
Institute
National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK)
Type
Method to Extend Research in Time (MERIT) Award (R37)
Project #
7R37DK012413-25
Application #
3482982
Study Section
Biochemistry Study Section (BIO)
Project Start
1991-09-30
Project End
1994-04-30
Budget Start
1991-09-30
Budget End
1992-04-30
Support Year
25
Fiscal Year
1991
Total Cost
Indirect Cost
Name
University of Pennsylvania
Department
Type
Schools of Medicine
DUNS #
042250712
City
Philadelphia
State
PA
Country
United States
Zip Code
19104
Loh, E; Rebbeck, T R; Mahoney, P D et al. (1999) Common variant in AMPD1 gene predicts improved clinical outcome in patients with heart failure. Circulation 99:1422-5
Hisatome, I; Morisaki, T; Kamma, H et al. (1998) Control of AMP deaminase 1 binding to myosin heavy chain. Am J Physiol 275:C870-81
Morisaki, H; Morisaki, T; Newby, L K et al. (1993) Alternative splicing: a mechanism for phenotypic rescue of a common inherited defect. J Clin Invest 91:2275-80
Morisaki, T; Holmes, E W (1993) Functionally distinct elements are required for expression of the AMPD1 gene in myocytes. Mol Cell Biol 13:5854-60
Sabina, R L; Fishbein, W N; Pezeshkpour, G et al. (1992) Molecular analysis of the myoadenylate deaminase deficiencies. Neurology 42:170-9
Morisaki, T; Gross, M; Morisaki, H et al. (1992) Molecular basis of AMP deaminase deficiency in skeletal muscle. Proc Natl Acad Sci U S A 89:6457-61
Mineo, I; Clarke, P R; Sabina, R L et al. (1990) A novel pathway for alternative splicing: identification of an RNA intermediate that generates an alternative 5' splice donor site not present in the primary transcript of AMPD1. Mol Cell Biol 10:5271-8
Moseley, W S; Morisaki, T; Sabina, R L et al. (1990) Ampd-2 maps to distal mouse chromosome 3 in linkage with Ampd-1. Genomics 6:572-4
Morisaki, T; Sabina, R L; Holmes, E W (1990) Adenylate deaminase. A multigene family in humans and rats. J Biol Chem 265:11482-6
Sabina, R L; Morisaki, T; Clarke, P et al. (1990) Characterization of the human and rat myoadenylate deaminase genes. J Biol Chem 265:9423-33

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