BIO2014-57518

Ref. BIO2014-57518

Acronym: PINR-sysmed

Title: Development of Bioinformatic tools to study the mechanisms of protein-interaction network rewiring: Application in systems medicine

Key words:
protein-protein interactions; protein interaction network; network rewiring in systems medicine; conditional network

Summary:

The systemic view of pathophenotypes has lead to the development of network-medicine. Network medicine relies on the insights of biological networks provided by the advances in network theory. Networks in biology are derived from the interactions between genes, transcripts, proteins and metabolites: protein-protein interactions (PPIs), gene-regulatory and metabolic networks. Complex disorders implicate products of multiple genes, acting cooperatively, involved in various biological processes that characterize the pathophenotype. Thus, the pathophenotype is the outcome of the perturbations in the underlying pathways, where gene products co-operate through various mechanisms such as PPIs. Network biology has proven its use in identifying candidate disease genes based on the guilt-by-association principle, which we recently used to predict new markers for the prognosis of some cancer metastases. The structural characterization of PPIs helps us to understand the mechanistic causes of the rewiring in a healthy network motivating a disorder. However, network rewiring is also a normal mechanism of regulation of a healthy cell. The modification of the sequence and/or conformation of a protein can affect an interaction either by direct changes in the binding region or through allosteric sites. Post-transcriptional modifications (PTMs) play a key role on the regulation of cell signalling by transiently changing protein interactions with mechanisms of switch-on and switch-off. Nowadays, that the first draft of the human proteome has been obtained by means of proteomic methods, the role of PTMs has become crucial to understand the mechanisms of regulation of interactions. The combined study of the dynamics of PPIs and PTMs has begun to reveal conditional rewiring of molecular networks through PTM-mediated recognition events. These studies highlight the utility of protein interaction networks (PINs) to functionally prioritize certain PTMs mapped in human cells, whereas the activity of some of them can cause a wide variety of human diseases. In this project we plan to study the mechanisms involved in the disruption and formation of PPIs and use it to analyze the rewiring of PINs caused by PTMs, mutations or splicing, specifically affecting human health. The study of this proposal is based in: 1) the analysis of the interface of known and modelled structures of PPIs to predict the strength of the interaction; and 2) the analysis of changes in regions outside the interface of a PPI that modify its prediction. In previous works we demonstrated the role of loop conformations to decide whether two proteins could interact or not. We plan to further study the role of residues outside the interface to improve the prediction of the association constant of two proteins and use it to predict if changes in sequence (or conformation) can disrupt an interaction and modify the network. The approach will be applied on the study of multifactorial diseases, such as cancer, and in general co-morbidities. We will analyze data from our collaborators, specifically for the analysis of brain metastasis from breast cancer, for co-morbidities between rhinitis, dermatitis and asthma, and in general co-morbidities with information retrieved from biomedical sources. Our final goal is to provide the tools helping researchers to analyze and predict the conditional rewiring of a PIN, caused by changes in the sequence or conformation of its proteins.


TECSPR13-1-0008

Fellow:  Dr. Narcis Fernández-Fuentes

ComPepts: Computational design of peptide disruptors of disease-associated protein interactions

Awards

 

2007 Drugs for Ageing. Award Pyme of “Red de Fundaciones Universidad-Empresa” for the collaboration in a Singular Specific Project (PSE) of Spanish Ministry of Science and Education (MEC) with Infociencia S.A.

 

2014 DREAM Challenge Award Best Performer in the DREAM 8.5:Rheumatoid Arthritis Responder Prediction Challenge". Sub-challenge 2

 

 

 

Old Grants

Búsqueda y caracterización automática de las posibles interacciones proteína-proteína como herramienta de ayuda al estudio de micro-matrices de DNA. Finance provider: Fundación Ramón Areces

BIO2002-03609 Desarrollo de modelos bioinformáticos para analizar interacciones entre proteínas en redes de señalización intracelulares: aplicación al estudio de MAP quinasas. Ministerio de Ciencia y Tecnologia & FEDER

Gaspar de Portolà Grant. Finance provider: CIRIT

INFOBIOMED: Structuring European Biomedical Informatics to Support Individualised Healthcare Finance provider: FP6-EC

Patogénesis de la metástasis del cáncer de mama: Análisis proteómico de rutas metabólicas influenciadas por Bcl-xL Finance provider: Redes de investigación cooperativa (FIS)

BIO2005-00533 Desarrollo de modelos bioinformáticos para analizar interacciones entre proteínas (II): Aplicaciones en la predicción de estructura y función de proteínas.Finance provider: Ministerio de Educación y Ciencia & FEDER

Evaluador de riesgo poblacional mediante análisis de microarrays e inteligencia artificial.FIT-350300-2006-40 Finance provider: Ministerio de Industria Turismo y Comercio ( PROFIT)

FIT-350300-2006-41 Prototipo de telemedicina para el seguimiento de alteraciones cardíacas y manchas sospechosas en la piel mediante terminales 3g comerciales y conexión umts. sistema prediagnóstico por inteligencia artificial y tecnologia grid. Ministerio de Industria Turismo y Comercio (PROFIT)

FIT-350300-2006-42 HAND-HEALTH FRIEND: Proyecto de investigación para el diseño de una nueva plataforma inteligente para el control de la salud personal y comunitaria sobre terminales móviles comerciales.Finance provider: Ministerio de Industria Turismo y Comercio (PROFIT)

ANEURIST Finance provider: European Commission FP6

PSE-010000-2007-1 Identificación de dianas secundarias y diseño de fármacos para enfermedades relacionadas con el envejecimiento mediante análisis estructural y funcional de rutas biológicas. Ministerio de Educación Ciencia & FEDER

FIT-350300-2007-72 Prototipo de telemedicina para el seguimiento de alteraciones cardíacas y manchas sospechosas en la piel mediante terminales 3g comerciales y conexión umts. sistema prediagnóstico por inteligencia artificial y tecnologia grid. Ministerio de Industria Turismo y Comercio ( PROFIT)

FIT-350300-2007-67 Evaluador de riesgo poblacional mediante análisis de microarrays e inteligencia artificial. Finance provider: Ministerio de Industria Turismo y Comercio ( PROFIT )

TSI-020100-2008-473 Playing Doctor: la revision médica completa en el PC domestco. Ealuación del sistema cardiovascular, respiratorio, auditivo, y otras afecciones de alta pre-valencia Finance provider: Ministerio de Industria Turismo y Comercio (PROFIT)

BIO2008-00205 Integración, análisis y modelado de redes de rutas biologicas: interaccion proteina-proteina, vias de señalización y regulación de la transcripcion. Finance provider: Ministerio de Educación y Ciencia & FEDER

TSI-020100-2009-89 Playing Doctor: la revision médica completa en el PC domestco. Ealuación del sistema cardiovascular, respiratorio, auditivo, y otras afecciones de alta pre-valencia Finance provider: Ministerio de Industria Turismo y Comercio (PROFIT)

PSE-010000-2009 Identificación de dianas secundarias y diseño de fármacos para enfermedades relacionadas con el envejecimiento mediante análisis estructural y funcional de rutas biológicas. Finance provider: Ministerio de Ciencia e Innovación & FEDER

AR2009-0015 Uso de la información mutual, derivada de la teoria de la información, para predecir interacci´n y coevolucion entre posiciones de una proteina y entre dos proteinas. Finance provider: Ministerio de Ciencia e Innovación

EUI2009-04018 Living with uninvited guests-comparing plant and animal responses to endocytic invasions (ERASysBio) Finance provider: Ministerio de Ciencia e Innovación programa de internacionalización. EC & FEDER

IMI -115002. eTOX: Integrating bioinformatics and chemoinformatics approaches for the development of expert systems allowing the in silico prediction of toxicities

CSD2009-00080 An integrated approach to post-transcriptional regulation of gene expression and its role in human disease. Finance provider: MICINN

BIO2011-22568 INTEGRATION, ANALISIS AND MODEL OF BIOLOGICAL PATHWAYS: SCORING FUNCTIONS FOR BIO-MOLECULAR INTERACTIONS AND GENOME WIDE ASSOCIATION STUDIES (GWAS). Finance provider: MINECO & FEDER

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