The objectives of research proposed here are continuations of those pursued by this laboratory over the past several years. (1) To apply biochemical and enzymological methodologies in the identification of molecular lesions in human blood cells associated with acquired or inherited human disease. (2) When such are identified, to define the clinical syndrome, conduct family studies where inherited lesions are involved and in such instances determine the mode of inheritance and the expression of the lesion in heterozygotes, hemizygotes, and homozygotes. (3) To determine the effects of the lesion on metabolic intermediates nucleotide pools, and cell morphology. (4) To extrapolate information obtained into further knowledge re normal regulation of metabolism. (5) To relate information derived from inherited """"""""experiments of nature"""""""" to physical and kinetic characteristics. (7) To develop methodology and expand existing techniques applicable to metabolic studies of human blood cells. Established technology in the laboratory permits assay of all enzymes of anaerobic glycolysis the hexose monophosphate shunt, many enzymes of nucleotide metabolism enzymes of glutathione synthesis and metabolism, and a considerable number of non-glycolytic enzymes including several pertinent to membrane phospholipids. (8) To utilize the spectrum of methodology available to study metabolic effects of reactive compounds potentially present in vivo or in the environment. Example: Effects of sulphydryl modifiers on enzyme catalysis, kinetics, thermostability; effects of lead. (9) To identify isozymes with differing metabolic properties and capabilities. (10) While erythrocyte metabolism has been a predominant concern, laboratory interests will not be confined to this cell type. For example, nucleotide metabolism in """"""""B"""""""" or """"""""T"""""""" lymphocyte cell lines is being studied in relation to immunodeficiency states associated with disturbed nucleotide metabolism and enzyme deficiency states.

Agency
National Institute of Health (NIH)
Institute
National Heart, Lung, and Blood Institute (NHLBI)
Type
Research Project (R01)
Project #
5R01HL012944-22
Application #
3334551
Study Section
Hematology Subcommittee 2 (HEM)
Project Start
1978-01-01
Project End
1992-12-31
Budget Start
1991-01-21
Budget End
1992-12-31
Support Year
22
Fiscal Year
1991
Total Cost
Indirect Cost
Name
University of California Los Angeles
Department
Type
Schools of Arts and Sciences
DUNS #
119132785
City
Los Angeles
State
CA
Country
United States
Zip Code
90095
Paglia, D E (1993) Acute episodic hemolysis in the African black rhinoceros as an analogue of human glucose-6-phosphate dehydrogenase deficiency. Am J Hematol 42:36-45
Valentine, W N; Paglia, D E (1990) Erythroenzymopathies and hemolytic anemia: the many faces of inherited variant enzymes. J Lab Clin Med 115:12-20
Paglia, D E; Valentine, W N; Nakatani, M et al. (1989) AMP deaminase as a cell-age marker in transient erythroblastopenia of childhood and its role in the adenylate economy of erythrocytes. Blood 74:2161-5
Valentine, W N; Paglia, D E; Nakatani, M et al. (1989) Inhibition of adenylate kinase by P1,P5-di(adenosine 5') pentaphosphate in assays of erythrocyte enzyme activities requiring adenine nucleotides. Am J Hematol 32:143-5
Valentine, W N; Herring, W B; Paglia, D E et al. (1988) Pyruvate kinase Greensboro. A four-generation study of a high K0.5s (phosphoenolpyruvate) variant. Blood 72:1054-9
Valentine, W N; Toohey, J I; Paglia, D E et al. (1987) Modification of erythrocyte enzyme activities by persulfides and methanethiol: possible regulatory role. Proc Natl Acad Sci U S A 84:1394-8
Ravindranath, Y; Paglia, D E; Warrier, I et al. (1987) Glucose phosphate isomerase deficiency as a cause of hydrops fetalis. N Engl J Med 316:258-61
Paglia, D E; Valentine, W N; Brockway, R A et al. (1987) Substrate specificity and pH sensitivity of deoxyribonucleotidase and pyrimidine nucleotidase activities in human hemolysates. Exp Hematol 15:1041-7
Paglia, D E; Valentine, W N; Miller, R E et al. (1986) Acute intravascular hemolysis in the black rhinoceros: erythrocyte enzymes and metabolic intermediates. Am J Vet Res 47:1321-5
Paglia, D E; Valentine, W N; Nakatani, M et al. (1986) Mechanisms of adenosine 5'-monophosphate catabolism in human erythrocytes. Blood 67:988-92

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