Juan HIDALGO

OBJETIVOS ESTRATÉGICOS

Los objetivos principales del grupo se centran en los mecanismos básicos de la neuroinflamación y el estrés oxidativo, con un énfasis particular en modelos animales de enfermedades neurodegenerativas como la enfermedad de Alzheimer y la esclerosis múltiple. Después de varios años usando ratones transgénicos producidos por otros investigadores, actualmente estamos produciendo nuestros propios ratones transgénicos (ratones KO condicionales).

LÍNEAS PRINCIPALES DE INVESTIGACIÓN

1. Papel de las citoquinas en el SNC.
Citoquinas como la IL-6 y el TNFα están implicadas en la respuesta del SNC al daño cerebral; mediante el uso de ratones transgénicos continuaremos nuestro análisis de su importancia, incluyendo el transcriptoma completo mediante microchips.

2. Modelos animales de la enfermedad de Alzheimer.
Uno de los modelos de la enfermedad de Alzheimer más usado es el ratón APP2576; la importancia del estrés oxidativo en este modelo se está evaluando analizando el fenotipo de los ratones APP2576 cruzados con ratones con una expresión alterada de la proteína antioxidante metalotioneína.

3. Modelos animales de esclerosis múltiple.
Existen varios modelos animales de EM, siendo la encefalitis autoinmune experimental (EAE) uno de los más estudiados. Evaluaremos la importancia de la citoquina IL-6 en este modelol.

4. Ejercicio y obesidad.
Evaluaremos la importancia de la citoquina IL-6 en la respuesta a ejercicio y a la obesidad inducida por dietas ricas en grasa mediante la generación de ratones KO tejido-específicos y en ratones con sobreexpresión cerebral de IL-6.

PUBLICACIONES

Hidalgo, J., Florit, S., Giralt, M., Ferrer, B., Keller, C. Pilegaard, H. Transgenic mice with astrocyte-targeted production of interleukin-6 are resistant to high-fat diet-induced increases in body weight and body fat. Brain, Behav. Immun. (2009) in press.

Huesa, G., Baltrons, M.A., Gómez-Ramos, P., Morán, A., García, A., Hidalgo, J., Francés, S., Santpere, G., Ferrer, I., Galea, E. Altered distribution of RhoA in Alzheimer´s disease and APP over-expressing mice. J. Alzheimer’s Dis. (2009) in press.

Badiola, N., Malagelada, C., Llecha, N., Hidalgo, J., Comella, J.X., Sabriá, J., Rodríguez-Álvarez, J. Activation of caspase-8 by tumour necrosis factor receptor 1 is necessary for caspase-3 activation and apoptosis in oxygen-glucose deprived cultured cortical cells. Neurobiol. Dis. 35 (2009) 438-447.

Valente, T., Hidalgo, J., Bolea, I., Ramírez, B., Anglés, N., Reguant, J., Morelló, J.R., Gutiérrez, C., Boada, M., Unzeta, M. A diet enriched in polyphenols and polyunsaturated fatty acids, LMN diet, induces neurogenesis in the subventricular zone and hippocampus of adult mouse brain. J. Alzheimer’s Dis. (2009) in press.

Quintana, A., Müller, M., Frausto, R.F., Ramos, R., Getts, D.R., Sanz, E., Hofer, M.J., Krauthausen, M., King, N.J.C., Hidalgo, J., Campbell, I.L. Site-specific production of interleukin-6 in the central nervous system retargets and enhances the inflammatory response in experimental autoimmune encephalomyelitis. J. Immunol. 183 (2009) 2079-2088.

Adhihetty, P.J., Uguccioni, G., Leick, L., Hidalgo, J., Pilegaard, H., Hood, D. The role of PGC-1α on mitochondrial function and apoptotic susceptibility in muscle. Am. J. Physiol. Cell. Physiol. 297 (2009) C217-C225.

Leick, L., Hellsten, Y., Fentz, J., Lyngby, S.S., Wojstaszewski, J.F.P., Hidalgo, J., Pilegaard, H. PGC-1α mediates exercise-induced skeletal muscle VEGF expression in mice. Am. J. Physiol. Endocrinol. Metab. 297 (2009) E92-E103.

Sanz, E., Quintana, A., Hidalgo, J., Marco, J.L., Unzeta, M. PF9601N [N-(2-propynyl)-2-(5-benzyloxy-indolyl) methylamine] confers MAO-B independent neuroprotection in ER stress-induced cell death. Mol. Cell. Neurosci. 41 (2009) 19-31.

Sanz, E., Quintana, A., Valente, T., Manso, Y., Hidalgo, J., Unzeta, M. Monoamine oxidase-B activity is not involved in the neuroinflammatory response elicited by a focal freeze injury. J. Neurosci. Res. 87 (2009) 784-794.

Molinero, A., Quintana, A., Penkowa, M., Hidalgo, J. Brain inflammation: Tumor necrosis factor receptors in mouse brain inflammatory responses. In: Encyclopedia of Neuroscience. Neuroimmunology. Binder, M.D., Hirokawa, N., Windhorst, U., Hirsch, M.C., Eds. (2008) Springer, Heidelberg, Germany, pp. 477-481.

Hidalgo, J., Chung, R., Penkowa, M., Vasak, M. Structure and function of vertebrate metallothioneins, in "Metallothioneins and Related Chelators", Vol. 5 of 'Metal Ions in Life Sciences'; Sigel, A., Sigel, H., Sigel, R.K.O., Eds. (2009) The Royal Society of Chemistry, Cambridge, UK, pp. 279-317.

Penkowa, M., Hidalgo, J., Aschner, M. Immune and inflammatory responses in the CNS: modulation by astrocytes. In: Chapter 13, Cytokines in Demyelinized Diseases, Neuroimmune Biology. Korneva, H.A., Phelps, C., Eds. (2008) Elsevier Academic Press, pp. 277-288.

Hidalgo, J., Metallothionein and brain inflammation, in: Metallothioneins in Biochemistry and Pathology. Zatta, P., Ed. (2008) World Scientific, New Jersey, pp. 71-91.

Chung, R.S., Penkowa, M., Dittmann, J., King, C.E., Bartlett, C., Asmussen, J.W., Hidalgo, J., Carrasco, J., Leung, Y.K.J., Walker, A.K., Fung, S.J., Dunlop, S.A., Fitzgerald, M., Beazley, L.D., Chuah, M.I., Vickers, J.C., West, A.K. Redefining the role of metallothioneins within the injured brain: extracellular metallothioneins play an important role in the astrocyte-neuron response to injury. J. Biol. Chem. 283 (2008) 15349-15358.

Vidal, E., Tortosa, R., Márquez, M., Serafín, A., Hidalgo, J., Pumarola, M. Infection of metallothionein 1+2 knockout mice with Rocky Mountain Laboratory scrapie. Brain Res. 1196 (2008) 140-150.

Leick, L., Wojtaszewski, J., Johansen, S., Kiilerich, K., Hellsten, Y., Comes, G., Hidalgo, J., Pilegaard, H. PGC-1α is not mandatory for exercise- and training-induced adaptive gene responses in mouse skeletal muscle. Am. J. Physiol. Endocrinol. Metab. 294 (2008) E463-E474.

Chung, R.S., Hidalgo, J., West, A. New insight into the molecular pathways of metallothionein-mediated neuroprotection and regeneration. J. Neurochem. 104 (2008) 14-20.

Sanz, E., Quintana, A., Battaglia, V., Toninello, A., Hidalgo, J., Ambrosio, S., Valotti, M., Marco, J.L., Tipton, K.F., Unzeta, M. Anti-apoptotic effect of MAO-B inhibitor PF9601N [N-(2-propynyl)-2-(5-benzyloxy-indolyl) methylamine] is mediated by p53 pathway inhibition in MPP+-treated SH-SY5Y human dopaminergic cells. J. Neurochem. 105 (2008) 2404-2417.

West, A.K., Hidalgo, J., Eddins, D., Levin, E.D., Aschner, M. Metallothionein in the central nervous system: Roles in protection, regeneration and cognition. Neurotoxicology 29 (2008) 488-502.

Quintana, A., Molinero, A., Borup, R., Nielsen, F.C., Campbell, I.L., Penkowa, M., Hidalgo, J.
Effect of astrocyte-targeted production of IL-6 on traumatic brain injury and its impact on the cortical transcriptome.
Dev Neurobiol. 68 (2008) 195-208.

Quintana, A., Molinero, A., Florit, S., Manso, Y., Comes, G., Carrasco, J., Giralt, M., Borup, R., Nielsen, F.C., Campbell, I.L., Penkowa, M., Hidalgo, J.
Diverging mechanisms for TNF-α receptors in normal mouse brains and in functional recovery after injury. From gene to behavior.
J. Neurosci. Res. 85 (2007) 2668-2685.

Westberg, J.A., Serlachius, M., Lankila, P., Penkowa, M., Hidalgo, J., Andersson, L.C.
Hypoxic preconditioning induces neuroprotective stanniocalcin-1 in brain via IL-6 signaling. Stroke 38 (2007) 1025-1030.

Mazzucotelli, A., Viguerie, N., Tiraby, C., Annicotte, J.S., Mairal, A., Klimcakova, E., Lepin, E., Delmar, P., Dejean, S., Tavernier, G., Lefort, C., Hidalgo, J., Pineau, T., Fajas, L., Clément, K., Langin, D.
The transcriptional coactivator peroxisome proliferator activated receptor (PPAR)gamma coactivator-1 alpha and the nuclear receptor PPAR alpha control the expression of glycerol kinase and metabolism genes independently of PPAR gamma activation in human white adipocytes.
Diabetes 56 (2007) 2467-2475.

Quintana, A., Giralt, M., Molinero, A., Campbell, I.L., Penkowa, M., Hidalgo, J.
Analysis of the cerebral transcriptome in mice subjected to traumatic brain injury. Importance of IL-6.
Neuroimmunomodulation. 2007;14(3-4):139-43.

Penkowa, M., Tio, L., Giralt, M., Quintana, A., Molinero, A., Atrian, S., Vasak, M., Hidalgo, J.
Specificity and divergence in the neurobiological effects of different metallothioneins after brain injury.
J. Neurosci. Res. 83 (2006) 974-984.

Latshaw, M.W., Glass, T., Parson, P., Hidalgo, J., Schwartz, B.
Predictors of blood mercury levels in older urban residents.
J. Occup. Environ. Med. 48 (2006) 715-722.

Reinecke, F., Levanets, O., Olivier, Y., Louw, R., Semete, B., Grobler, A., Hidalgo, J., Smeitnik, J., Olckers, A., Van Der Westhuizen, F.H.
Metallothionein-IIa expression is inducible and protects against ROS-mediated cell death in rotenone treated HeLa cells.
Biochem. J. 395 (2006) 405-415.

Hidalgo, J., Penkowa, M., Espejo, C., Martínez-Cáceres, E.M., Carrasco, J., Quintana, A., Molinero, A., Florit, S., Giralt, M., Ortega-Aznar, A.
Expression of metallothionein-I&II and III in Alzheimer disease and animal models of neuroinflammation.
Exp. Biol. Med. 231 (2006) 1450-1458.

Penkowa, M., Cáceres, M., Borup, R., Nielsen, F.C., Poulsen, C.B., Quintana, A., Molinero, A., Carrasco, J., Florit, S., Giralt, M., Hidalgo, J.
Novel Roles for Metallothionein-I+II (MT-I+II) in Defense Responses, Neurogenesis and Tissue Restoration after Traumatic Brain Injury: Insights from global gene expression profiling in wildtype and MT-I+II knockout mice.
J. Neurosci. Res. 84 (2006) 1452-1474.

Carrasco, J., Adlard, P., Cotman, C., Quintana, A., Penkowa, M., Xu, F., Van Nostrand, W., Hidalgo, J.
Metallothionein-I&III expression in animal models of Alzheimer disease.
Neuroscience 143 (2006) 911-922.

Novak, J.P., Kim, S.-Y., Xu, J., Modlich, O., Volsky, D.J., Honys, D., Slonczewski, J.L., Bell, D.A., Blattner, F.R., Blumwald, E., Boerma, M., Cosio, M., Gatalica, Z., Hajduch, M., Hidalgo, J., Mcinnes, R.R., Miller Iii, M.C., Penkowa, M., Rolph, M.S., Sottosanto, J., St-Arnaud, R., Szego, M.J., Twell, D., Wang, C.
Generalization of DNA microarray dispersion properties: microarray equivalent of t-distribution.
Biol. Direct 1 (2006) 27.

Ruderman, N.B., Keller, C., Richard, A.-M., Saha, A.K., Luo, Z., Xiang, X., Giralt, M., Ritov, V.B., Kelley, D.E., Hidalgo, J., Pedersen, B., Kelly, M.
Interleukin-6 regulation of AMPK: Potential role in the systemic response to exercise and prevention of the metabolic syndrome.
Diabetes 55 (2006) S48.

Poulsen, C.B., Penkowa, M., Borup, R., Nielsen, F.C., Cáceres, M., Quintana, A., Molinero, A., Carrasco, J., Giralt, M., Hidalgo, J. Brain response to traumatic brain injury in wild type and IL-6 knockout mice: a microarray analysis.
J. Neurochem. 92 (2005) 417-432.

Penkowa, M., Keller, P., Keller, C., Hidalgo, J., Giralt, M., Pedersen, B.K.
Exercise-induced metallothionein expression in human skeletal muscle fibers.
Exp. Physiol. 90 (2005) 477-486.

Keller, P., Penkowa, M., Keller, C., Steensberg, A., Fischer, C.P., Giralt, M., Hidalgo, J., Pedersen, B.K.
Interleukin-6 receptor expression in contracting human skeletal muscle: regulating role of IL-6.
Faseb. J. 19 (2005) 1181-1183.

Scheede-Bergdahl, C., Penkowa, M., Hidalgo, J., Olsen, D.B., Schjerling, P., Plough, T., Boushel, R., Dela, F.
Metallothionein-mediated antioxidant defense system and its response to exercise training are impaired in human type 2 diabetes.
Diabetes 54 (2005) 3089-3094.

Quintana, A., Giralt, M., Rojas, S., Penkowa, M., Campbell, I.L., Hidalgo, J., Molinero, A.
Differential role of TNF-receptors in mouse brain inflammatory responses in cryolesion brain injury.
J. Neurosci. Res. 82 (2005) 701-716.

Hidalgo, J.
Respuesta del sistema nervioso central a lesiones traumáticas: papel de las proteínas antioxidantes metalotioneínas.
Ciencia al Día Internacional 5 (2004) 1-12.

Hidalgo, J.
Astrocyte metallothioneins and physiological and pathological consequences to brain injury.
In: The Role of Glia in Neurotoxicity, Second Edition. Aschner, M., Costa, L., eds. (2004) CRC Press LLC, Boca Raton, pp. 191-205

Hidalgo, J.
Metallothioneins And Brain Injury: What Transgenic Mice Tell Us.
Environ. Hlth. Prev. Med. 9 (2004) 87-94.

Penkowa, M., Quintana, A., Carrasco, J., Giralt, M., Molinero, A., Hidalgo, J.
Metallothionein prevents neurodegeneration and CNS cell death after treatment with gliotoxin 6-aminonicotinamide.
J. Neurosci. Res. 77 (2004) 35-53.

Kelly, M., Keller, C., Avilucea, P.R., Keller, P., Luo, Z., Xiang, X., Giralt, M., Hidalgo, J., Saha, A.K., Pedersen, B.K., Ruderman, N.B. AMPK activity is depressed in tissues of the IL-6 knockout mice: the effect of exercise. Biochem. Biophys. Res. Commun. 320 (2004) 449-454.

Keller, C., Giralt, M., Hidalgo, J., Pedersen, B.K.
Exercise normalises over-expression of TNF- in knockout mice.
Biochem. Biophys. Res. Commun. 321 (2004) 179-182.

Penkowa, M., Florit, S., Giralt, M., Quintana, A., Molinero, A., Carrasco, J., Hidalgo, J.
Metallothionein reduces CNS inflammation, neurodegeneration and cell death following kainic acid-induced epileptic seizures.
J. Neurosci. Res. 79 (2004) 522-534.

Group Leader:
Juan Hidalgo Pareja
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TEL: +34 935 812 037

Group Members:
Javier Carrasco Trancoso
Gemma Comes Orpinell Mercè Giralt Carbonell
Jazmina Manso Sanz
Amalia Molinero Egea
Albert Quintana Romero
Lorena Ramírez Corpas
Raquel Ramos Hidalgo
Beatriz Ferrer Villahoz
Maria Erta Cañabate
Rosa Tridico
Marco Castro