This application is for continued support of a Program Project Grant in an NICHD-funded Mental Retardation Research Center (MRRC). The program, whose goal is to better understand the biochemical defects and pathogenesis of inborn errors that cause mental retardation, developmental disabilities, or other forms of central nervous system dysfunction, or early death, comprises five projects bound by focus, orientation, and research techniques. Disorders to be studied are glutaric acidemia type I, glutaric acidemia type II, defects of mitochondrial iron transport and storage, cystathionine beta-synthase (CBS) deficiency, and propionic acidemia. The investigators, Drs. Goodman, Kraus, Frerman and Koeller, have contiguous laboratories in the MRRC; share interests, methods, and equipment, and interact informally and in seminars and journal clubs on a daily basis. The first project will investigate Dr. Koeller's biochemical and molecular aspects of glutaric acidemia type 1 (GA1) and D-2-hydroxy-glutaric acidemia, both of which cause severe damage to the central nervous system in early life, and will seek to create a murine model of GA1. Dr. Koeller's project will investigate biochemical and molecular aspects of iron transport and storage in human mitochondria, disturbances of which cause Friedreich's ataxia and X-linked sideroblastic anemia and ataxia. One of Dr. Kraus' projects will examine biochemical and molecular aspects of electron flavoprotein-ubiquinone oxidoreductase (ETF-QO), the inner mitochondrial membrane protein whose deficiency is a cause of glutaric acidemia. The other project will study several aspects of CBS structure, function, and tissue distribution, including transcriptional and post-transcriptional regulation, and will examine an available murine model of CBS deficiency. The last project will extend investigations on the structure, function and regulation of the propionyl-CoA carboxylase A and B genes, and on the structure and function of the enzyme itself. The thread that unites these projects is the attempt to better understand the role these enzymes and pathways play in different tissues, how the enzyme defects cause disease, and how the diseases can be treated in a more rational manner.

Agency
National Institute of Health (NIH)
Institute
Eunice Kennedy Shriver National Institute of Child Health & Human Development (NICHD)
Type
Research Program Projects (P01)
Project #
5P01HD008315-28
Application #
6738051
Study Section
Pediatrics Subcommittee (CHHD)
Program Officer
Vitkovic, Ljubisa
Project Start
1979-04-01
Project End
2006-04-30
Budget Start
2004-05-01
Budget End
2006-04-30
Support Year
28
Fiscal Year
2004
Total Cost
$1,292,744
Indirect Cost
Name
University of Colorado Denver
Department
Pediatrics
Type
Schools of Medicine
DUNS #
041096314
City
Aurora
State
CO
Country
United States
Zip Code
80045
Fielding, Alistair J; Usselman, Robert J; Watmough, Nicholas et al. (2008) Electron spin relaxation enhancement measurements of interspin distances in human, porcine, and Rhodobacter electron transfer flavoprotein-ubiquinone oxidoreductase (ETF-QO). J Magn Reson 190:222-32
Jiang, Hua; Rao, K Sudhindra; Yee, Vivien C et al. (2005) Characterization of four variant forms of human propionyl-CoA carboxylase expressed in Escherichia coli. J Biol Chem 280:27719-27
Moat, Stuart J; Bao, Liming; Fowler, Brian et al. (2004) The molecular basis of cystathionine beta-synthase (CBS) deficiency in UK and US patients with homocystinuria. Hum Mutat 23:206
Chloupkova, Maja; Reaves, Scott K; LeBard, Linda M et al. (2004) The mitochondrial ABC transporter Atm1p functions as a homodimer. FEBS Lett 569:65-9
Chloupkova, Maja; LeBard, Linda S; Koeller, David M (2003) MDL1 is a high copy suppressor of ATM1: evidence for a role in resistance to oxidative stress. J Mol Biol 331:155-65
Chloupkova, Maja; Maclean, Kenneth N; Alkhateeb, Asem et al. (2002) Propionic acidemia: analysis of mutant propionyl-CoA carboxylase enzymes expressed in Escherichia coli. Hum Mutat 19:629-40
Jones, Patricia M; Tjoa, Susan; Fennessey, Paul V et al. (2002) Addition of quantitative 3-hydroxy-octadecanoic acid to the stable isotope gas chromatography-mass spectrometry method for measuring 3-hydroxy fatty acids. Clin Chem 48:176-9
Janosik, M; Oliveriusova, J; Janosikova, B et al. (2001) Impaired heme binding and aggregation of mutant cystathionine beta-synthase subunits in homocystinuria. Am J Hum Genet 68:1506-13
Maclean, K N; Janosik, M; Oliveriusova, J et al. (2000) Transsulfuration in Saccharomyces cerevisiae is not dependent on heme: purification and characterization of recombinant yeast cystathionine beta-synthase. J Inorg Biochem 81:161-71
Ravn, K; Chloupkova, M; Christensen, E et al. (2000) High incidence of propionic acidemia in greenland is due to a prevalent mutation, 1540insCCC, in the gene for the beta-subunit of propionyl CoA carboxylase. Am J Hum Genet 67:203-6

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