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.
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