Estudio del papel de la quinasa ATR en envejecimiento y cáncer (desarrollo de un modelo murino)

Tesis doctoral inédita leía en la Universidad Autónoma de Madrid, Facultad de Ciencias, Departamento de Biología Molecular. Fecha de lectura: 25-05-2010Seckel Syndrome is a rare human disease characterized by growth retardation and microcephaly. Previous findings have linked Seckel to deficient signalling of the ATR kinase, which is in charge of safeguarding genomic integrity under conditions of replicative stress. We have generated a murine model of the disease, bypassing the early lethality of ATR absence, by means of a humanized allele in which a splicing defect significantly reduces the levels of the protein. This model, fully recapitulates the symptoms observed in human patients of the disease; moreover, the analysis of this model has revealed novel disorders derived from a deficiency in ATR. We not only described these disorders but also tried to understand their origins and physiological impact. Importantly, Seckel embryos display massive amounts of replicative stress, which decrease to marginal levels in the tissues of the adult mouse. Despite this decrease in the amount of stress, mutant mice die early due to the development of a severe progeroid phenotype, leading us to propose that the replicative stress suffered during embryogenesis becomes a critical determinant of the lifespan and overall fitness of mammalian organisms. The Seckel phenotypes including the progeria were further accelerated in the absence of p53. The study of the mechanism responsible for this effect suggests a synthetic lethal interaction between ATR and p53, opening the possibility to study the relevance of using ATR inhibitors for the selective elimination of p53-deficient tumours. Based upon these observations, we investigated whether the synthetic lethal effect observed between low ATR levels and p53 loss were also present in the context of additional cancerous mutations that accelerate replication rates. To this end, we evaluated the potential role of ATR in the abrogation of lymphomagenesis induced by c-Myc. Our study suggests that ATR inhibition might be a suitable approach for the elimination of Myc driven tumours. Altogether, we here provide the first alive model for ATR studies in a mammal, which has allowed us to reach important conclusions on the role of replicative stress on cancer and ageing

Estudio de desarrollo espontaneo de colonias de Triatoma dimidiata en ecotopos artificiales y determinación del flujo genético entre grupos silvestres, peridomiciliados y domiciliados mediante análisis molecular, morfométrico y de receptores antenales

IP 1204-05-10273v.1. Informe final v.2. ficha tecnica del informe final.ARTICULO(S) EN REVISTA: Genetic stucture of silvatic, peridomestic and domestic populations of Triatoma;dimidiata from a specific area of Boyaca, Colombia / C. Ramirez,C.A. Jaramillo, P. Delgado, n. Pinto, G.;Aguilera, F. Guhl. -- En: Acta tropica. -- Vol. 83, suplemento(2002); p.S84. -- ISSN 0001706X

Caracterización antigénica de poblaciones de trypanosoma rangeliaisladasen ciclos de transmisión doméstica y silvestre en Colombia :

IP 1105-05-279-99Guhl. -- En: Mem inst Oswaldo Cruz. -- Vol. 96, no. 8 (nov. 201); p. 1043-1048. -- Molecular characterization;and diagnosis of trypanosoma cruzi and T. rangeli / FelipeGuhl,Carlos Jaramillo, Julio Cesar Carranza,;Gustavo Adolfo Vallejo. -- En: Archives of medical research. --No. 33 (2002); p. 362-370. -- kDNA markers;define two major trypanosoma rangeli lineages in latin America/Gustavo Adolfo Vallejo, Felipe Guhl, Julio;Cesar Carranza, Leyder Elena Lozano, Jorge L. Sanchez, Jose C.Jaramillo,Diego Gualtero, Nadia Castañeda,;Julio C. Silva, Mario Steindel. -- En: Acta tropica. -- No. 81(2002); p.77-82. -- Short technical reports:;Hybridization screening of very short PCR products for paleoepidemiological studies of chagas disease. -- En:;Biotechniques. -- No. 30 (Jan. 2001); p. 102-109. -- Parity betwen kinetoplast DNA and mini exon gene;sequences supports either clonal evolution or speciation in trypanosoma rangeli strains isolated from rhodnius;colombiensis, R. pallescens and R. prolixus in Colombia /Gustavo adolfo Vallejo, Felipe Guhl, Julio Cesar;Carranza, Jaime Moreno, Omar Triana, Edmundo Carlos Grisard. --En: Infection genetics and evolution. -- No.;67 (2002); p. 1-7. -- PONENCIA(S) EN CONGRESO: Caracterizacionantigenicade cepas trypanosoma rangeli;aisladas en ciclos de transmision domestica y silvestre enareasendemicasde Colombia / Carlos Alberto Aya,;Andrea Arevalo, Daniel Urrea, Jorge Garcia, Derly Yara, LeyderE. Lozano,Julio C. Carranza, Gustavo A. -- En:;ARTICULO(S) EN REVISTA: Amplification of a specific repetitiveDNA sequence for trypanosoma rangeli;identification and its potential application in epidemiologicalinvestigations / Nancy Vargas, Ricardo P.;Souto, Julio Cesar Carranza, Gustavo Adolfo Vallejo, Bianca Zingales. -- En: Experimental parasitology. -- No.;96 (2000); p. 147-159. -- Chagas disease and human migration /Felipe Guhl, Carlos Jaramillo, Gustavo Adolfo;Vallejo, Felipe Cardenas, A. Arroyo, Arthur Aufderheide. -'- Vol.95, no. 4(jul.-ago. 2000); p. 553-555. --;Differentiation and genetic analysis of rhodnius prolixusandrhodnius colombiensis by rDNA and RAPD;amplification / Carlos Jaramillo, Maria Fernanda Montaña,LydaRaquel Castro, Gustavo Adolfo Vallejo, Felipe;de la Universidad del Tolima / Julio Cesar Carranza M., LeyderElena Lozano, Gustavo Adolfo Vallejo. -- En:;Sistemas de Informacion Geografica, Sensores Remotos y GeneticaPoblacional de Vectores y Parasitos Aplicados;al Control de la Enfermedad de Chagas / Curso Taller Internacional Sistemas de Informacion Geografica,;Sensores Remotos y Genetica Poblacional de Vectores y ParasitosAplicadosal Control de la Enfermedad de;Chagas (2002 dic. 2-6 : Bogotá) ; Editores Felipe Guhl, CarlosJaramillo.'-- Bogotá : Universidad de Los;Andes, c2002. -- 224 p. : il., mapas, tablas ; 28 cm. -- ISBN9583437021.;Congreso Nacional de Ciencias Biologicas (37 : 2002 oct. 1-4 :San Juan dePasto). -- San Juan de Pasto :;Universidad de Nariño, 2002. -- 28 cm. -- MEMORIA(S): Laboratorio de investigaciones en parasitologia tropica