Abstract
(English)
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The project EUGINDAT is an integrated approach that links genetics, biochemistry, physiology, genomics, proteomics, structural biology, drug development and clinical studies in an attempt to improve understanding and treatment of Primary Inherited Aminoacidurias (PIA). PIA are rare diseases involving defects in renal reabsorption of amino acids that also affect other organs. The generation of amino acid or peptide transporter-deficient mice will have an impact on our knowledge not only of renal reabsorption but also nutrition, and pathological states such as certain forms of cachexia and selected disorders of the central nervous system. The main objectives are: 1) To complete a clinical and molecular-genetic description of PIA with the generation of a European PIA-DATABASE including: Cystinuria, Lysinuric Protein Intolerance (LPI), Dicarboxylic Aminoaciduria (DA), Hartnup Disorder (HDis), Iminoglycinuria (IG) and 'unlabeled aminoacidurias'. The proposal aims to study candidate genes for cystinuria, DA, HDis and IG. 2) To gain a thorough knowledge of the molecular structure of relevant transporters using 2D crystals of prokaryotic, and eventually eukaryotic, homologues and 3D crystals of water-soluble extra cellular domains. 3) To complete a functional genomic study of relevant transporters underlying PIA and renal reabsorption of amino acids at three levels: i) identification of transporters with a role in the trans-epithelial transport of amino acids in the proximal tubule OK cell model, ii) generation of KO mice, and iii) identification of polymorphisms (SNPs) in renal transporters that show association with renal reabsorption of amino acids in genetically isolated human populations. 4) To identify genes and/or loci that affect cystinuria lithiasis, and may eventually explain gender-related and individual variability in stone-forming activity in patients with cystinuria. 5) To develop new therapeutic strategies for cystinuria lithiasis. 6) To identify the mechanism.
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