Lesch Nyhan Disease (LND) represents an ideal model human disease in which to study the mechanisms by which even single gene defects produce very complex disruptions of normal genomic, proteomic, biochemical and metabolomic changes function. LND is a thoroughly characterized but poorly understood metabolic and neurobehavioral disorder characterized by metabolic and neurological dysfunction and caused by mutations in the gene that encodes the purine reutilization enzyme HPRT. Although much is known about the effects of HPRT deficiency on purine metabolism, there is little understanding of the mechanisms responsible for the complex disease phenotype. We therefore propose to bring together the interests and expertise of a number of investigators at the University of California San Diego and Johns Hopkins University to undertake a broad systems networks and pathways approach to this disorder through the transoriptional, proteomic, biochemical developmental, metabolomic effects of HPRT deficiency in both the mammalian and the yeast model systems. The investigators included in this project have long individual histories of major advances to the problem of HPRT deficiency and to the development of technologies such as human proteome characterization, computational approaches to metabolomic studies and utilization of the yfeast model system for characterization of genetic aberrations in human disease. We shall unify these approaches into an integrated program in an attempt to identify and understand the mechanisms that tie the purine defect to the complex HPRT deficiency disease phenotype.

National Institute of Health (NIH)
National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK)
Resource-Related Research Projects (R24)
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Special Emphasis Panel (ZDK1-GRB-W (O2))
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Mckeon, Catherine T
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University of California San Diego
Schools of Medicine
La Jolla
United States
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Guibinga, Ghiabe-Henri (2015) MicroRNAs: tools of mechanistic insights and biological therapeutics discovery for the rare neurogenetic syndrome Lesch-Nyhan disease (LND). Adv Genet 90:103-31
Dammer, Eric B; Göttle, Martin; Duong, Duc M et al. (2015) Consequences of impaired purine recycling on the proteome in a cellular model of Lesch-Nyhan disease. Mol Genet Metab 114:570-579
Fu, Rong; Ceballos-Picot, Irene; Torres, Rosa J et al. (2014) Genotype-phenotype correlations in neurogenetics: Lesch-Nyhan disease as a model disorder. Brain 137:1282-303
Hu, Jianfei; Rho, Hee-Sool; Newman, Robert H et al. (2014) PhosphoNetworks: a database for human phosphorylation networks. Bioinformatics 30:141-2
Guibinga, Ghiabe-Henri; Barron, Nikki; Pandori, William (2014) Striatal neurodevelopment is dysregulated in purine metabolism deficiency and impacts DARPP-32, BDNF/TrkB expression and signaling: new insights on the molecular and cellular basis of Lesch-Nyhan Syndrome. PLoS One 9:e96575
Woodard, Crystal L; Goodwin, C Rory; Wan, Jun et al. (2013) Profiling the dynamics of a human phosphorylome reveals new components in HGF/c-Met signaling. PLoS One 8:e72671
Newman, Robert H; Hu, Jianfei; Rho, Hee-Sool et al. (2013) Construction of human activity-based phosphorylation networks. Mol Syst Biol 9:655
Uzoma, Ijeoma; Zhu, Heng (2013) Interactome mapping: using protein microarray technology to reconstruct diverse protein networks. Genomics Proteomics Bioinformatics 11:18-28
Kang, Tae Hyuk; Park, Yongjin; Bader, Joel S et al. (2013) The housekeeping gene hypoxanthine guanine phosphoribosyltransferase (HPRT) regulates multiple developmental and metabolic pathways of murine embryonic stem cell neuronal differentiation. PLoS One 8:e74967
Sutandy, F X Reymond; Qian, Jiang; Chen, Chien-Sheng et al. (2013) Overview of protein microarrays. Curr Protoc Protein Sci Chapter 27:Unit 27.1

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