Instituto Aragones Of Ciencias Of La Salud

La Línea de la Concepción, Spain

Instituto Aragones Of Ciencias Of La Salud

La Línea de la Concepción, Spain

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Grant
Agency: European Commission | Branch: FP7 | Program: CP-FP | Phase: HEALTH.2012.2.4.5-2 | Award Amount: 7.85M | Year: 2012

We propose a collaborative effort to advance our understanding of the inflammatory bowel diseases Ulcerative Colitis and Crohns Disease and to increase diagnostic precision in detection of the diseases in their early manifestation. We will utilize the largest collection of samples so far assembled of treatment nave patients recently diagnosed with inflammatory bowel disease, a total of 400 patients. The material will be extensively analyzed for DNA methylation status, RNA transcription profile, protein markers and gut microbial content in order to create a molecular snapshot of IBD in its early manifestation. As control group, material from a total of 200 recently by endoscopy diagnosed non-inflammatory but symptomatic patients (symptomatic non-IBD) as well as 200 healthy, age-matched, non-smoking, controls without any known first relatives diagnosed with IBD, will be collected and used. All patients will be diagnosed according to standardized diagnostic criterias, characterized using current known clinical markers as well as genotyped for known susceptibility loci. This large, well characterized cohort in conjunction with our proposed massive molecular profiling will yield a list of biomarkers indicative for onset of the disease. Based on the finding within the project assays capable of analyzing panels of relevant protein markers and methods for rapid profiling of gut microbial content relevant for IBD will be developed by participating SME:s, offering large commercial potential. The proposed biomarkers will form a solid ground for development of improved diagnostic assays and be a rich source to mine for novel therapeutic targets.


Guallar D.,Instituto Aragones Of Ciencias Of La Salud | Perez-Palacios R.,Instituto Aragones Of Ciencias Of La Salud | Climent M.,University of Zaragoza | Martinez-Abadia I.,University of Zaragoza | And 7 more authors.
Nucleic Acids Research | Year: 2012

Rex1/Zfp42 is a Yy1-related zinc-finger protein whose expression is frequently used to identify pluripotent stem cells. We show that depletion of Rex1 levels notably affected self-renewal of mouse embryonic stem (ES) cells in clonal assays, in the absence of evident differences in expression of marker genes for pluripotency or differentiation. By contrast, marked differences in expression of several endogenous retroviral elements (ERVs) were evident upon Rex1 depletion. We demonstrate association of REX1 to specific elements in chromatin-immunoprecipitation assays, most strongly to muERV-L and to a lower extent to IAP and musD elements. Rex1 regulates muERV-L expression in vivo, as we show altered levels upon transient gain-and-loss of Rex1 function in pre-implantation embryos. We also find REX1 can associate with the lysine-demethylase LSD1/KDM1A, suggesting they act in concert. Similar to REX1 binding to retrotransposable elements (REs) in ES cells, we also detected binding of the REX1 related proteins YY1 and YY2 to REs, although the binding preferences of the two proteins were slightly different. Altogether, we show that Rex1 regulates ERV expression in mouse ES cells and during pre-implantation development and suggest that Rex1 and its relatives have evolved as regulators of endogenous retroviral transcription. © 2012 The Author(s).


Casas P.,University of Zaragoza | Ascaso F.J.,University of Zaragoza | Ascaso F.J.,Instituto Aragones Of Ciencias Of La Salud | Vicente E.,University of Zaragoza | And 3 more authors.
Graefe's Archive for Clinical and Experimental Ophthalmology | Year: 2013

Objective: To assess the peripapillary retinal nerve fiber layer (RNFL) thickness, optic nerve head (ONH) morphologic parameters, and macular thickness and volume in patients affected by obstructive sleep apnea-hypopnea syndrome (OSAHS). Methods: This prospective, observational case-control study consisted of 96 eyes of 50 OSAHS patients (mean age of 50.9 ± 12.4 years, best-corrected visual acuity ≥20/20, refractive error less than 3 spherocylindrical diopters, and intraocular pressure <21 mmHg) who were enrolled and compared with 64 eyes of 33 age-matched controls. Peripapillary RNFL thickness, ONH parameters, macular thickness and volume were measured by optical coherence tomography (OCT). Results: OSAHS patients showed a significant reduction of the nasal quadrant RNFL thickness (74.7 ± 15.8 μm) compared with those values observed in control patients (81.1 ± 16.6 μm, p = 0.047, Student's t-test). No differences in peripapillary RNFL thickness were observed when dividing the OSAHS group in accordance with disease severity. Vertical integrated rim area (VIRA) (0.67 ± 0.41 mm 3 in OSAHS vs 0.55 ± 0.29 mm3 in controls; p = 0.043, Student's t-test), horizontal integrated rim width (HIRW) (1.87 ± 0.31 mm2 in OSAHS vs 1.8 ± 0.25 mm2 in controls; p = 0.039, Student's t-test) and disc area (2.74 ± 0.62 mm2 in OSAHS vs 2.48 ± 0.42 mm2 in controls; p = 0.002, Student's t-test) showed significant differences, all of them being higher in the OSAHS group. Severe OSAHS had significant higher disc area (2.8 ± 0.7 mm 2) than controls (2.5 ± 0.4 mm2; p = 0.016, ANOVA test). Temporal inner macular thickness was significantly higher in mild-moderate OSAHS patients (270 ± 12 μm) than in severe OSAHS patients (260 ± 19 μm; p = 0.021, ANOVA test). Conclusions: OSAHS patients showed decreased peripapillary nasal RNFL thickness, and increased ONH area and volume parameters when they were evaluated by OCT. These findings suggest that neuronal degeneration might be present in the retina of OSAHS patients, as previously observed in some neurodegenerative disorders © 2013 Springer-Verlag Berlin Heidelberg.


Moros M.,University of Zaragoza | Hernaez B.,Instituto Nacional Of Investigacion Y Tecnologia Agraria Y Alimentaria | Garet E.,NanoImmunoTech SL | Dias J.T.,University of Zaragoza | And 6 more authors.
ACS Nano | Year: 2012

Magnetic nanoparticles (NPs) hold great promise for biomedical applications. The core composition and small size of these particles produce superparamagnetic behavior, thus facilitating their use in magnetic resonance imaging and magnetically induced therapeutic hyperthermia. However, the development and control of safe in vivo applications for NPs call for the study of cell-NP interactions and cell viability. Furthermore, as for most biotechnological applications, it is desirable to prevent unspecific cell internalization of these particles. It is also crucial to understand how the surface composition of the NPs affects their internalization capacity. Here, through accurate control over unspecific protein adsorption, size distribution, grafting density, and an extensive physicochemical characterization, we correlated the cytotoxicity and cellular uptake mechanism of 6 nm magnetic NPs coated with several types and various densities of biomolecules, such as glucose, galactose, and poly(ethylene glycol). We found that the density of the grafted molecule was crucial to prevent unspecific uptake of NPs by Vero cells. Surprisingly, the glucose-coated NPs described here showed cellular uptake as a result of lipid raft instead of clathrin-mediated cellular internalization. Moreover, these glucose-functionalized NPs could be one of the first examples of NPs being endocytosed by caveolae that finally end up in the lysosomes. These results reinforce the use of simple carbohydrates as an alternative to PEG molecules for NPs functionalization when cellular uptake is required. © 2012 American Chemical Society.


Grant
Agency: European Commission | Branch: FP7 | Program: MC-ERG | Phase: PEOPLE-2007-2-2.ERG | Award Amount: 45.00K | Year: 2009

Oxidative phosphorylation (OXPHOS) is the metabolic process that provides most of the energy usable by the cells. OXPHOS couples two sets of reactions, respiration and ATP synthesis. Respiration consists in the sequential transfer of electrons carried out by the mitochondrial respiratory chain (MRC) complexes I (CI), II (CII), III (CIII), and IV (CIV). The proton gradient generated during respiration is used by the ATP synthase (CV). The components of the OXPHOS system, localized in the inner mitochondrial membrane, are large heteromeric enzymes whose subunits are encoded in two separated genomes, the nuclear and mitochondrial (mt) DNAs. The assembly of these subunits into the complete complexes is an intricate process in which many factors must interplay. In addition, it has been proved that CI, CIII and CIV interact with each other giving rise to supercomplexes (also called respirasomes). It has been determined that many mitochondrial disorders result in an altered assembly of one or several components of the MRC. However, many aspects of the mechanisms underlying the molecular defects in these disorders are still unknown. Therefore, it is necessary to investigate the assembly processes and the involved factors, in order to get a deeper understanding on OXPHOS biogenesis that will shed light on the pathogenetic mechanisms underlying the mitochondrial disorders caused by defective complex assembly. The objectives of the study will be: 1) to determine the entry point of the mtDNA-encoded CI subunits in the assembly process of this complex, which remains to be established; 2) to determine the order of events and the involved factors in the assembly process of human and mouse CIII which has not been studied yet in mammalian systems and 3) to study the factors and processes that determine the interaction between the individual complexes in the formation of the supercomplexes and the physiological relevance of these interactions for the activity of the OXPHOS system.


Grant
Agency: European Commission | Branch: FP7 | Program: CSA-SA | Phase: REGPOT-2009-2 | Award Amount: 1.16M | Year: 2010

Tuberculosis (TB) accounts amongst the most deadly infectious diseases worldwide. Despite the availability of a vaccine and effective drugs, Mycobacterium tuberculosis, the etiologic agent of TB, still defies the humanity. An alarming increase in drug resistance and emergence of outbreaks has made it urgent the need for increased surveillance and control. With its structured global geographical distribution, it becomes increasingly clear that this pathogen could have established an advantageous association with its host. Such region-specific host-pathogen equilibrium argues for a TB control at a regional level. The overall objective of the present proposal consists in establishing a network connecting leading institutions in the field from the three North African countries (Morocco, Algeria, and Tunisia) and Europe. The aim is to upgrade the research and surveillance capacity potential of these Europes most neighboring Mediterranean partner countries (MPC) through know-how sharing, two-way experience exchange, training, joint research activities, and equipment upgrading. By reinforcing existing human and technological resources in the targeted MPCs, the planned activities will contribute to better address the host and pathogen key factors governing TB transmission/expansion dynamics, emergence of drug resistance, and host susceptibility. This will endow MPCs with higher capacity to better unveil the molecular mechanisms leading to the prevailing epidemiological situation in the specific regional context. Since TB is a health threat common to both sides of the Mediterranean Sea, which is amplified through consistent population migration flows, the planned cooperative initiative could also positively impact on TB control in Europe. Ultimately, dissemination of the projects results will foster the MPCs institutional visibility and scientific competitiveness, allowing them to be more integrated for participation to future European framework program calls.


Grant
Agency: European Commission | Branch: FP7 | Program: CP-FP | Phase: HEALTH-2009-3.2-2 | Award Amount: 3.40M | Year: 2010

ECHO, European Collaboration for Healthcare Optimization, gathers the interests for Healthcare Performance Measurement of different Academic and Research Institutions from six European countries and an International Body for Healthcare Policy Analysis. Designed as a 48 months project, it has been conceived as a pilot study based on available administrative databases. It aims at describing the actual performance of six different Healthcare Systems at hospital, healthcare area, regional and country level. To tackle performance measurement in this project, two different methodological approaches will be used: [a] a population geographical-based, responding the question: Is the access to a diagnostic or surgical procedure dependant on the place where a person lives? And, [b] a provider-specific, answering the question: Is the risk for a patient to access high quality care -and have better health outcomes- different regarding the provider in which he or she is admitted? Utilization, equity in access and allocative efficiency will be analysed as performance measures in the former approach; and, healthcare outcomes and associated costs will be measures in the latter one. ECHO has been envisaged as a five work packages project. The first two work packages are devoted to prepare the core work package (WP#3) Performance Measurement and Report; so, the WP#1 is committed with the creation of the ECHO Data Warehouse and the second one is dedicated to the Methodological foundations of the project. Work packages #4 (web-based tools development) and #5 (dissemination) are carefully thought to ease the diffusion of our findings to decision-makers; in the former, a web-based analytical tool will allow advanced users to replicate methods and analysis; in the latter, local key agents like policy decision-makers and managers, will feed the findings making them transferable to their own decision-making process.


Grant
Agency: European Commission | Branch: FP7 | Program: MC-CIG | Phase: FP7-PEOPLE-2012-CIG | Award Amount: 100.00K | Year: 2012

The objectives of the project are to identify and evaluate potassium channels of the KCa3.1/KCa2.X type as novel drug targets for the prevention and treatment of cerebrovascular ischemia and neuroprotection in metabolic disease and neurodegenerative disorders associated with vascular pathologies, as a new pathophysiological concept and treatment strategy. To reach these aims, the proponent employs genetic models of ion channel deficiency and experimental models of human disease for pharmacological interventions with highly selective small molecule modulators and performs target identification studies on human material. The project will be conducted within the research frame of the Aragonese Institute of Health Sciences and in collaboration with clinical departments of the University Hospital Miguel Servet in Zaragoza, Spain, and the University Hospital Odense, Denmark, and with neuroscientists and pharmacologists at the University of Southern Denmark and the University of California, Davis, United States, for optimal scientific synergy and use of resources. The 1st and 2nd work packages consist of electrophysiological, molecular biological, and imaging studies using genetic and pharmacological tools for target identification in cerebrovasculature from murine and human diabetes mellitus type 2 (DM-2), Alzheimer disease (AD), and Morbus Fabry. The 3nd of work package consists of intervention trials and the testing the efficacy of recently developed small molecule modulators in mice models of DM-2 and AD for target validation. The 4th work package consists of epidemiological studies in which we define the genetic variability and polymorphisms in KCa3.1/KCa2.3 genes in Aragon Workers Health Study (AWHS)-cohort and evaluate their potential predictive value for disease. Our conceptually new approach and the outcome of our study may provide the rationale to develop small molecule modulators of KCa3.1/KCa2.X for the treatment of cerebrovascular and neurological disease.


Grant
Agency: European Commission | Branch: FP7 | Program: MC-CIG | Phase: FP7-PEOPLE-2011-CIG | Award Amount: 100.00K | Year: 2012

Metabolic Syndrome (MetS) is closely linked to disturbances in lipid and glucose metabolism and increases the risk of developing cardiovascular disease and diabetes. One-fourth of the adult European population has the MetS and a further increase is anticipated because a greater prevalence of obesity in the future. Apolipoprotein E (APOE) associates with lipoproteins and mediates theirmetabolism. In humans, the APOE gene is polymorphic and has three alleles, APOE*2, APOE*3 and APOE*4. Carrying the APOE*4 allele has been associated with an increased cardiovascular risk, predisposition to develop Alzheimers disease and insulin resistance. Recently, APOE*4 has also been linked with MetS. However, the mechanisms whereby this association occurs are not clear. The objective of this project is to investigate the role of APOE in metabolic syndrome. We hypothesize that APOE*4 presence determines a less flexible metabolism; i.e. an inability to effectively switch between lipids and carbohydrates for fuel and the subsequent carbohydrate intolerance. For our Work Package 1 we will employ mice whose endogenous Apoe gene has been replaced by the human APOE*3 or APOE*4 allele. We will investigate the energy substrate handling of these humanized mice at the whole body level by using metabolite tracers and diverse -omics, which will reveal why the energy generating pathways differ with apoE-isoform presence. At the population level, Work Package 2 will identify human APOE*4 carriers and investigate new APOE genetic variants to determine whether the association between APOE-isoform and metabolic syndrome is diet-dependent in the participants of the Aragon Workers Health Study, an ongoing longitudinal study targeted to study the appearance and progression of cardiovascular risk factors. By translating basic science into human studies, this project will provide new targets to prevent or treat the onset of MetS and its associated morbimortality in European populations


Grant
Agency: European Commission | Branch: H2020 | Program: MSCA-IF-EF-ST | Phase: MSCA-IF-2014-EF | Award Amount: 158.12K | Year: 2015

Liver transplantation is currently the only proven therapy to extend life of patients with terminal liver disease. Organ bioengineering and regenerative medicine are promising new technologies that can help reduce the burden of liver shortage by increasing the number of organs available for transplantation. However, current bioengineered livers lack a functional vascular network that can readily allow their transplantation into a living host. Previous studies by the candidate have shown successful recellularization of acellular liver scaffolds using endothelial cells and hepatic cells in a perfusion bioreactor, creating a vascularized human liver organoid. However, its vascular network was unable to maintain vascular patency under constant blood flow for long periods of time. Hence, better understanding of how experimental cell seeding conditions of porcine liver scaffolds influence their re-vascularization efficiency is critical to achieve sustainable vascular patency after transplantation. In order to accomplish this, the impact of fluid flow pressure and the seeded cell number will be investigated in re-endothelialization efficiency of an acellular porcine liver scaffold. Furthermore, bioreactor pre-conditioning with fluid flow pressure ramping and sequential cycles of vascular growth and maturation will be used to induce re-vascularization, maturation, and enhanced function to potentially increase vascular patency. Finally, re-vascularized liver scaffolds will be transplanted into 5-10Kg pigs and short and long-term vascular patency will be investigated. Hence, the long-term objective of this project is to create a functional re-vascularized porcine liver scaffold, a critical first step towards the effective transplantation of bioengineered livers.

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