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Projects. Life and Earth Sciences

Pathological mechanisms in Lysinuria with protein intolerance

Lead Researcher:
Manuel Palacín Prieto

Research Centre:
Instituto de Investigación Biomédica (IRB). Barcelona.

Sinopsis: 

Manuel Palacín PrietoObjectives 1 to 3: these objectives connect with the role of alveolar macrophages in the development of pulmonary alveolar proteinosis in LPI, and which depend on the establishment of the first animal model of lysinuria with protein intolerance (LPI) (conditional KO mouse for y+LAT1). Initial studies show that, under different nutritional conditions, these mice present a phenotype that is similar to human LPI, although different in that these mice present very little reduction in the renal re-absorption of lysine, suggesting that other transporters (probably y+LAT2) compensate for the ablation of the y+LAT1 transporter. Currently, attempts are being made to prove this compensation exists, and experimental strategies are being perfected to evaluate the intestinal absorption of amino acids in y+LAT1 KO mice. Together with all of this it is hoped to send the model for publication in the first quarter of 2013. Following the establishment of the model, the study of the maturation of macrophages by GM-CSF will commence. These studies are being undertaken by Dr. Bodoy.

Objective 4: In connection with the atomic structure of the y+LAT1 transporter. Highly significant advances have been achieved here, with diffractions up to 6‑8 Å with protein 6 crystals, giving 30% identity of amino acid sequence with human y+LAT1 transporter, which is mutated in LPI. To facilitate better diffractions, Dr. Errasti will spend 6 months at the laboratory of Prof. Christine Ziegler (MPI-Biophysics Frankfurt), where the structure of the BetP prokaryotic transporter has been resolved in 6 different forms. On the other hand, thanks to the work of Dr. Bartoccioni it is known that protein 6 is an exchanger of neutral amino acids in the small side chain. This is a major advance because to date this protein, which has been crystallised, had an unknown function. The transporter function of protein 6 will aid study of the impact of the mutations in LPI on the structure and function of the y+LAT1 transporter (Objective 5).

 

Researcher's web address:
http://www.irbbarcelona.org/index.php/en 



Manuel Palacín Prieto

He studied Biology in the University of Barcelona (UB) and received his doctorate from the University of Alcalá de Henares (1983) for his work on the transport of nutrients in the placenta under the direction of Professor Miguel Ángel Lasunción and Professor Emilio Herrera (Ramón y Cajal Hospital, Madrid). He was Tenured Professor of Physiology in the Faculty of Medicine in the University of Extremadura (1984-86), where he studied the role of Meister's cycle in the transport of amino acids in the placenta with Prof. José Viña. In the period from 1986-1987 he studied the zoning of the hepatic metabolism of fructose 2,6-biphosphate with Prof. Joseph Katz (Cedars Sinai Medical Center, Los Angeles, CA, USA). Tenured Professor (1987) of Biochemistry and Molecular Biology (BQBM) in the UB, combining his teaching with a collaboration with Prof. Heini Murer (University of Zurich) cloning the heavy rBAT chain, thereby discovering the Heteromeric Aminoacid Transporters (HAT) (1992). BQBM Professor in the UB (1995). In Barcelona he identified two genes for cystinuria and the gene for lysinuria with protein intolerance (1999). He is Group Head in the IRB Barcelona (2002), where he is resolving the atomic structure of a prokaryote homologue of the light subunits of the HAT (2011).


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