The overall objective of the proposed research is to delineate the molecular bases of the marked phenotypic variability in Gaucher disease (GD), a prototype inborn error of metabolism. The proposed studies address the hypotheses: 1) The mutations that predispose to GD are associated with disruptions of acid B-glucosidase [glucosylceramide (GC) glucohydrolase; UCase: GBA locus] structure and function leading to differential threshold levels of enzymatic activity in various patient tissues. Although this is a major basis of the phenotypic spectrum, intra- and inter- locus sequence variants and polymorphisms may provide for additional contexts for phenotypic expression of disease-related mutations, e.g., altered substrate flux. To understand the interplay of such sequence variations, the determinants for the control of normal and mutant GCase enzyme activities will be evaluated with liposomal (in vitro) and lysosomal (ex vivo) membrane binding systems. 2) The in vivo levels of specific substrate synthesis and degradation, e.g., GC synthase (GCS) expression, and hydrolase activity, in selected inborn errors of glycosphingolipid (GSL) metabolism are primary determinants of their regional, tissue or cellular pathophysiology. The functional polymorphic variation at the GCS and GCase loci and the relationships of these variations to defined phenotypic parameters will be determined in patients with GD type 1. As a corollary, effective enzyme or gene therapy in GD, as a prototype, requires specific levels of enzyme in various organs. 3) The lack of adequate mouse models for GD have been a major impediment to continuing progress in pathophysiologic understanding and therapeutic developments, and their creation and characterization is a major focus of this proposal. We have developed conditional (tetracycline-on) and fixed (five specific point mutations) GCase expressing mice to simulate human GD variants. These alternative systems, together with the GCS KO heterozgyote mice will be used to address GC flux in relation to phenotype in vivo. These studies should provide insights into the pathophysiology and therapy of GD, and to over 20 glycolipid storage diseases that depend on the GCS synthetic and GCase degradative pathwavs.

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National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK)
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Medical Biochemistry Study Section (MEDB)
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Mckeon, Catherine T
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Cincinnati Children's Hospital Medical Center
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Dai, Mei; Liou, Benjamin; Swope, Brittany et al. (2016) Progression of Behavioral and CNS Deficits in a Viable Murine Model of Chronic Neuronopathic Gaucher Disease. PLoS One 11:e0162367
Burrow, Thomas A; Sun, Ying; Prada, Carlos E et al. (2015) CNS, lung, and lymph node involvement in Gaucher disease type 3 after 11 years of therapy: clinical, histopathologic, and biochemical findings. Mol Genet Metab 114:233-241
Sun, Ying; Florer, Jane; Mayhew, Christopher N et al. (2015) Properties of neurons derived from induced pluripotent stem cells of Gaucher disease type 2 patient fibroblasts: potential role in neuropathology. PLoS One 10:e0118771
Kitatani, Kazuyuki; Wada, Masayuki; Perry, David et al. (2015) Activation of p38 Mitogen-Activated Protein Kinase in Gaucher's Disease. PLoS One 10:e0136633
Dasgupta, Nupur; Xu, You-Hai; Li, Ronghua et al. (2015) Neuronopathic Gaucher disease: dysregulated mRNAs and miRNAs in brain pathogenesis and effects of pharmacologic chaperone treatment in a mouse model. Hum Mol Genet 24:7031-48
Barnes, Sonya; Xu, You-Hai; Zhang, Wujuan et al. (2014) Ubiquitous transgene expression of the glucosylceramide-synthesizing enzyme accelerates glucosylceramide accumulation and storage cells in a Gaucher disease mouse model. PLoS One 9:e116023
Xu, You-hai; Xu, Kui; Sun, Ying et al. (2014) Multiple pathogenic proteins implicated in neuronopathic Gaucher disease mice. Hum Mol Genet 23:3943-57
Liou, Benjamin; Haffey, Wendy D; Greis, Kenneth D et al. (2014) The LIMP-2/SCARB2 binding motif on acid ?-glucosidase: basic and applied implications for Gaucher disease and associated neurodegenerative diseases. J Biol Chem 289:30063-74
Pandey, Manoj Kumar; Jabre, Nicholas A; Xu, You-Hai et al. (2014) Gaucher disease: chemotactic factors and immunological cell invasion in a mouse model. Mol Genet Metab 111:163-71
Watson, Carey L; Mahe, Maxime M; MĂșnera, Jorge et al. (2014) An in vivo model of human small intestine using pluripotent stem cells. Nat Med 20:1310-4

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