For the past 15 years this Program has focused has focused on genetic disorders of peroxisome biogenesis and function. In recent years understanding of the biogenesis and metabolic functions of peroxisomes has expanded significantly. Thirteen of the known 16 peroxisomal genetic disorders manifest mental retardation but the connection between peroxisomal abnormality and mental retardation is still unknown. The peroxisome has been shown to have a much wider range of functions than has been recognized in the past. This Program Project has been characterized by a strong synergism between clinical and basic science and this interaction will continue. The projects and investigators of the proposed Program Project will interface with related basic research projects and with ongoing clinical trials (Moser). Our clinics have identified more than 5000 patients with peroxisomal disorders. While they continue to provide a framework for this proposal, new information will be derived from several mouse and yeast models of peroxisomal biogenesis, function and disease. The present proposal includes 4 projects in addition to administrative and clinical, biochemical,, cell, and molecular cores. The first Project (Smith) will determine the function of the X-linked of the X-linked adrenoleukodystrophy (XALD) protein, explore causes of the marked clinical heterogeneity that typifies this disease and test therapeutic modalities in an ALD mouse model. The second Project (Watkins) will investigate the role of fatty acid activating enzymes in XALD and their role in the regulation of very long chain fatty acid homeostasis, particularly in the brain. The third Project (Gould) will resolve outstanding questions related to peroxisome biogenesis genetics and disorders and elucidate the biochemistry of a-oxidation and its disorders. The fourth Project (Valle) will use yeast and mouse models to investigate the role of peroxisomal membrane proteins in peroxisome biogenesis, function, and disease.

Agency
National Institute of Health (NIH)
Institute
Eunice Kennedy Shriver National Institute of Child Health & Human Development (NICHD)
Type
Research Program Projects (P01)
Project #
5P01HD010981-29
Application #
7111159
Study Section
Pediatrics Subcommittee (CHHD)
Program Officer
Oster-Granite, Mary Lou
Project Start
1978-01-01
Project End
2007-06-30
Budget Start
2006-07-01
Budget End
2007-06-30
Support Year
29
Fiscal Year
2006
Total Cost
$1,488,284
Indirect Cost
Name
Hugo W. Moser Research Institute Kennedy Krieger
Department
Type
DUNS #
155342439
City
Baltimore
State
MD
Country
United States
Zip Code
21205
Brose, Rebecca Deering; Shin, Gloria; McGuinness, Martina C et al. (2012) Activation of the stress proteome as a mechanism for small molecule therapeutics. Hum Mol Genet 21:4237-52
Brose, Rebecca Deering; Avramopoulos, Dimitri; Smith, Kirby D (2012) SOD2 as a potential modifier of X-linked adrenoleukodystrophy clinical phenotypes. J Neurol 259:1440-7
Steinberg, S J; Snowden, A; Braverman, N E et al. (2009) A PEX10 defect in a patient with no detectable defect in peroxisome assembly or metabolism in cultured fibroblasts. J Inherit Metab Dis 32:109-19
Jia, Zhenzhen; Pei, Zhengtong; Maiguel, Dony et al. (2007) The fatty acid transport protein (FATP) family: very long chain acyl-CoA synthetases or solute carriers? J Mol Neurosci 33:25-31
Watkins, Paul A; Maiguel, Dony; Jia, Zhenzhen et al. (2007) Evidence for 26 distinct acyl-coenzyme A synthetase genes in the human genome. J Lipid Res 48:2736-50
Jia, Zhenzhen; Moulson, Casey L; Pei, Zhengtong et al. (2007) Fatty acid transport protein 4 is the principal very long chain fatty acyl-CoA synthetase in skin fibroblasts. J Biol Chem 282:20573-83
Eichler, Florian; Mahmood, Asif; Loes, Daniel et al. (2007) Magnetic resonance imaging detection of lesion progression in adult patients with X-linked adrenoleukodystrophy. Arch Neurol 64:659-64
Lu, Jyh-Feng; Barron-Casella, Emily; Deering, Rebecca et al. (2007) The role of peroxisomal ABC transporters in the mouse adrenal gland: the loss of Abcd2 (ALDR), Not Abcd1 (ALD), causes oxidative damage. Lab Invest 87:261-72
Moser, Hugo W; Mahmood, Asif; Raymond, Gerald V (2007) X-linked adrenoleukodystrophy. Nat Clin Pract Neurol 3:140-51
Moser, Hugo W (2006) Therapy of X-linked adrenoleukodystrophy. NeuroRx 3:246-53

Showing the most recent 10 out of 167 publications