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Project Objectives
The main objectives are:
- To complete a clinical and genetic description of Primary Inherited Aminoacidurias (PIA) with the generation of a DATA BASE for PIA (PIADATABASE) including the following: cystinuria (MIM 220100 and 600918), lysinuric protein intolerance (LPI or hyperdibasic aminoaciduria type 2, or familial protein intolerance; MIM 222700), dicarboxylic aminoaciduria (DA; MIM 222730), Hartnup disorder (HDis; MIM 234500), iminoglycinuria (IG; MIM 242600) and “unlabeled aminoacidurias” (UnAA). The proposal includes the study of candidate genes for cystinuria, DA, HDis and IG.
- To acquire a thorough knowledge of the molecular structure of relevant transporters for PIA and renal reabsorption of amino acids with the study of 2D crystals of prokaryotic homologues and 3D crystals of the extracellular domain of the heavy subunit of HATs.
- To complete a functional genomic study of relevant transporters for PIA and renal reabsorption of amino acids at three levels: i) identification of amino acid transporters that play a role in the trans-epithelial transport of amino acids in the tubular OK cell model, ii) generation of KO mice models, and iii) identification of polymorphisms (SNPs) in renal amino acid and peptide transporters that may eventually show association with the variability in the renal reabsorption of amino acids in genetically isolated human populations.
- To identify genes and/or genetic loci that affect cystinuria lithiasis, and may eventually explain gender and individual variability in the stone-forming activity in patients with cystinuria.
- To develop new therapeutic strategies for cystinuria lithiasis. This will be developed at three levels: i) prospective study with thiola and/or D-penicillamine dosage depending on urine free cystine levels. ii) Screening of 5 new drugs to treat cystine lithiasis in bo,+AT KO mice. iii) Proof of principle for a misfolding therapy of cystinuria due to trafficking defects of rBAT mutations.
- To identify the mechanisms of pathology in LPI which explain the hepatic phenotype (hyperammonemia) and the immune system-compromising related phenotype, which may result in new therapeutic approaches for this disease, and to test new therapeutic protocols for LPI.