Molecular and Cellular Mechanisms Driving Cardiovascular Disease in Hutchinson-Gilford Progeria Syndrome: Lessons Learned from Animal Models.

Hutchinson-Gilford progeria syndrome (HGPS) is a rare genetic disease that recapitulates many symptoms of physiological aging and precipitates death. Patients develop severe vascular alterations, mainly massive vascular smooth muscle cell loss, vessel stiffening, calcification, fibrosis, and generalized atherosclerosis, as well as electrical, structural, and functional anomalies in the heart. As a result, most HGPS patients die of myocardial infarction, heart failure, or stroke typically during the first or second decade of life. No cure exists for HGPS, and therefore it is of the utmost importance to define the mechanisms that control disease progression in order to develop new treatments to improve the life quality of patients and extend their lifespan. Since the discovery of the HGPS-causing mutation, several animal models have been generated to study multiple aspects of the syndrome and to analyze the contribution of different cell types to the acquisition of the HGPS-associated cardiovascular phenotype. This review discusses current knowledge about cardiovascular features in HGPS patients and animal models and the molecular and cellular mechanisms through which progerin causes cardiovascular disease.This study was supported by grants to V.A. from the Spanish Ministerio de Ciencia e Innovación (MCIN) (PID2019-108489RB-I00) and the Instituto de Salud Carlos III (ISCIII) (grant AC17/00067, as coordinator of the E-Rare Joint Transnational call 2017 project “TREAT-HGPS,” European Union Horizon 2020 Framework Programme) with co-funding from the European Regional Development Fund (ERDF, “A way to build Europe”), the Progeria Research Foundation (Award PRF 2019–77), and the Fundación Marató TV3 (38/C/2020). I.B. was supported by the Comunidad Autónoma de Madrid (grant 2017-T1/BMD-5247). The CNIC is supported by the MCIN, the ISCIII, and the Pro CNIC Foundation.S

Interrelación entre proteínas asociadas a uniones intercelulares estrechas, polaridad de los hepatocitos y el virus de la hepatitis C

Tesis doctoral inédita leída en la Universidad Autónoma de Madrid, Facultad de Medicina, Departamento de Bioquímica. Fecha de lectura: 17 de Junio de 201

Progeria: a perspective on potential drug targets and treatment strategies.

Work in the V.A. laboratory is supported by the Spanish Ministerio de Ciencia e Innovación (MCIN)/Agencia Estatal de Investigación (AEI)/ 10.13039/501100011033 (grant PID2019-108489RB-I00) with co-funding from the European Regional Development Fund (‘A way to build Europe’), Fundació la Marató TV3 (grant 202033), the Progeria Research Foundation (PRF) (award PRF 2019–77), and Asociación Progeria Alexandra Peraut. Work in the M.O.B. lab is supported by grants from the PRF, Center for Innovative Medicine (Karolinska Institutet), and the Swedish Research Council. I.B. is supported by the Comunidad Autónoma de Madrid (grant 2017-T1/BMD-5247). The CNIC is supported by the MCIN, the Instituto de Salud Carlos III, and the Pro-CNIC Foundation and is a Severo Ochoa Center of Excellence (grant CEX2020-001041-S funded by MCIN/AEI/ 10.13039/501100011033).S

Caveolin-1 deficiency induces a MEK-ERK1/2-Snail-1-dependent epithelial-mesenchymal transition and fibrosis during peritoneal dialysis

Peritoneal dialysis (PD) is a form of renal replacement therapy whose repeated use can alter dialytic function through induction of epithelial-mesenchymal transition (EMT) and fibrosis, eventually leading to PD discontinuation. The peritoneum from Cav1-/- mice showed increased EMT, thickness and fibrosis. Exposure of Cav1-/- mice to PD fluids further increased peritoneal membrane thickness, altered permeability and increased the number of FSP-1/cytokeratin-positive cells invading the sub-mesothelial stroma. High-throughput quantitative proteomics revealed increased abundance of collagens, FN and laminin, as well as proteins related to TGF- activity in matrices derived from Cav1-/- cells. Lack of Cav1 was associated with hyperactivation of a MEK-ERK1/2-Snail-1 pathway that regulated the Smad2-3/Smad1-5-8 balance. Pharmacological blockade of MEK rescued E-cadherin and ZO-1 inter-cellular junction localization, reduced fibrosis and restored peritoneal function in Cav1-/- mice. Moreover, treatment of human PD-patient-derived MCs with drugs increasing Cav1 levels, as well as ectopic Cav1 expression, induced reacquisition of epithelial features. This study demonstrates a pivotal role of Cav1 in the balance of epithelial versus mesenchymal state and suggests targets for the prevention of fibrosis during PD

Coronary and carotid artery dysfunction and KV7 overexpression in a mouse model of Hutchinson-Gilford progeria syndrome.

Hutchinson-Gilford progeria syndrome (HGPS) is an extremely rare genetic disease caused by expression of progerin, a lamin A variant that is also expressed at low levels in non-HGPS individuals. Although HGPS patients die predominantly from myocardial infarction and stroke, the mechanisms that provoke pathological alterations in the coronary and cerebral arteries in HGPS remain ill defined. Here, we assessed vascular function in the coronary arteries (CorAs) and carotid arteries (CarAs) of progerin-expressing LmnaG609G/G609G mice (G609G), both in resting conditions and after hypoxic stimulus. Wire myography, pharmacological screening, and gene expression studies demonstrated vascular atony and stenosis, as well as other functional alterations in progeroid CorAs and CarAs and aorta. These defects were associated with loss of vascular smooth muscle cells and overexpression of the KV7 family of voltage-dependent potassium channels. Compared with wild-type controls, G609G mice showed reduced median survival upon chronic isoproterenol exposure, a baseline state of chronic cardiac hypoxia characterized by overexpression of hypoxia-inducible factor 1α and 3α genes, and increased cardiac vascularization. Our results shed light on the mechanisms underlying progerin-induced coronary and carotid artery disease and identify KV7 channels as a candidate target for the treatment of HGPS.Work supported by Ministerio de Ciencia e Innovación (MCIN) and Agencia Estatal de Investigación (AEI) (MCIN/AEI/https:// doi. org/ 10. 13039/ 50110 00110 33 grants SAF2016-79490-R and PID2019-108489RB-I00), with cofunding from Fondo Social Europeo (“El FSE invierte en tu futuro”), and a donation from Asociación Progeria Alexandra Peraut. Microscopy was conducted at the Microscopy & Dynamic Imaging Unit, CNIC, ICTS-ReDib, co-funded by MCIN/AEI/https:// doi. org/ 10. 13039/ 50110 00110 33. R.M.N was supported by the Ministerio de Educación, Cultura y Deporte (pre-doctoral contract FPU16/05027), and I.B. is supported by the Comunidad Autónoma de Madrid (grants 2017- T1/BMD-5247 and 2021-5A/BMD-20944), and the Ramón y Cajal contract (RYC2021-033805-I) funded by MCIN/ AEI/10.13039/501100011033 and the European Union “Next- GenerationEU”/PRTR. The CNIC is supported by the MCIN, the Instituto de Salud Carlos III, the Pro-CNIC Foundation, and is a Severo Ochoa Center of Excellence (grant number CEX2020-001041-S funded by MCIN/AEI/https:// doi. org/ 10. 13039/ 50110 00110 33).N

Association of gene-enviroment and age of pre-onset cannabis use with age at onset of psychosis in frist-episode patients

Trabajo presentado a la 10ª Reunión anual de la Sociedad Española de Investigación sobre Cannabinoides celebrada en Santander del 26 al 28 de noviembre de 2009.Es conocida la influencia negativa del uso de cannabis sobre el curso y pronóstico de la esquizofrenia. El cannabis es, además, la sustancia de abuso más utilizada en pacientes con esquizofrenia (15%-65%). Sin embargo sólo una pequeña proporción de consumidores de cannabis desarrollan psicosis. Varios estudios han demostrado que el uso de cannabis precede al debut de la psicosis en varios años (entre 4 y 5 ). El inicio precoz del consumo de cannabis en la adolescencia, puede por tanto, estar asociado a un debut precoz de la psicosis, con el consiguiente pronóstico negativo de la enfermedad. Varios polimorfismos de nucleótidoúnico (SNPs) del gen que codifica el receptor CB1 (CNR1; rs806379, rs1535255, rs2023239 y rs1049353) han sido asociados al consumo de drogas o alcohol (Zhang et al., Molecular Psychiatry, 9, 916–931. 2004, Schmidtetal., 2002 Drug and Alcohol Dependence, 65, 221–224) Variaciones en el gen de la triptófano hidroxilasa se han asociado con un mayor riesgo de psicosis (LiD, HeL: Hum Genet 2006). Finalmente, algunos de los SNPs en los receptores de la serotonina se han asociado con diversos trastornos psiquiátricos como la esquizofrenia o la depresión, sin embargo, los resultados de estos estudios de asociación genética han mostrado resultados conflictivos.Peer Reviewe

Mejora del clima de clase y resolución de conflictos raciales y étnicos a través de la intervención en la organización y la metodología de las sesiones de Educación Física

Este trabajo de investigación se ha realizado en Zaragoza capital, concretamente en el Instituto de Enseñanza Secundaria María Moliner, centro al que acuden alumnos con importantes problemas de marginación social e inmigración. Mediante el desarrollo del Proyecto “Mejora del clima de clase y resolución de conflictos raciales y étnicos a través de la intervención en la organización y la metodología de las sesiones de Educación Física” se ha pretendido optimizar los procesos organizativos y metodológicos del área de Educación Física en aras de una mejora del nivel de convivencia y clima de clase, así como estrategias de resolución de conflictos específicos. En este sentido, se ha intervenido sobre el tratamiento de los contenidos del área de la Educación Física, tanto en el aula como en los recreos, para un mejor desarrollo de la competencia básica social y ciudadana y de los contenidos transversales. Los resultados obtenidos son optimistas e indican que es posible modificar ciertas conductas nocivas, aunque se hace necesario continuar con las intervenciones para consolidar actitudes positivas de respeto y convivencia, así como saludables

A Disrupted-in-Schizophrenia 1 Gene Variant is Associated with Clinical Symptomatology in Patients with First-Episode Psychosis

OBJECTIVE: DISC1 gene is one of the main candidate genes for schizophrenia since it has been associated to the illness in several populations. Moreover, variations in several DISC1 polymorphisms, and in particular Ser704Cys SNP, have been associated in schizophrenic patients to structural and functional modifications in two brain areas (pre-frontal cortex and hippocampus) that play a central role in the genesis of psychotic symptoms. This study tested the association between Ser704Cys DISC1 polymorphism and the clinical onset of psychosis. METHODS: Two hundred and thirteen Caucasian drug-naive patients experiencing a first episode of non-affective psychosis were genotyped for rs821616 (Ser704Cys) SNP of the DISC1 gene. The clinical severity of the illness was assessed using SAPS and SANS scales. Other clinical and socio-demographic variables were recorded to rule out possible confounding effects. RESULTS: Patients homozygous for the Ser allele of the Ser704Cys DISC1 SNP had significantly (p<0.05) higher rates at the positive symptoms dimension (SAPS-SANS scales) and hallucinations item, compared to Cys carriers. CONCLUSION: DISC1 gene variations may modulate the clinical severity of the psychosis at the onset of the disorde