Oncogenes, programmed cell death and gene expression. The discovery of activated RAS genes in human cancer in 1982 concept of the cellular oncogene and triggered an intense effort to understand their biochemistry and biology. For this reasons, for my PhD (1991-1996) I decided to join this hot topic of research to study the role of ras family proteins on signalling pathways leading to cell proliferation under the supervision of Dr. Juan Carlos Lacal (CSIC). My thesis work contributed to support phospholipase D as target of RAS and revealed a role for RHO members, a sub-family of RAS, in the promotion of metastasis (https://www.ncbi.nlm.nih.gov/pubmed/9444953). After completing my PhD, I joined Dr. Nuñez's lab at University of Michigan (MI, USA) for posdoctoral training (1996-1999). Dr. Nuñez's group was working on the identification of the molecules involved in the process of apoptosis, an exciting new topic at that time. Exploiting my background on signal transduction, I proposed a project to gain insight on the mechanisms by which growth factors supress cell death. This work uncovered the first link between extracellular signals and the apoptosis machinery and resulted in a seminal publication describing the PI3K/Akt/BAD axis (https://www.ncbi.nlm.nih.gov/pubmed/9381178). Next, aiming to identify new molecules regulated by the PI3K/Akt pathway, we found a transcription factor, FKHR, whose activity was regulated in response to extracellular signals through this pathway (https://www.ncbi.nlm.nih.gov/pubmed/10602488). This study sparked my interest in the regulation of gene expression and accepted a job position at the Hospital de La Princesa where Dr. Landazuri’s group was starting a research line on the Hypoxia Inducible Factor (HIF), a transcription factor responsible for the cellular adaptation to chronic hypoxia. Thus, in 2000, I started my our research group on the biology of hypoxia. Firstly, capitalizing on my background, we investigated the effect of hypoxia on the induction of apoptosis (https://www.ncbi.nlm.nih.gov/pubmed/11294857)and the (lack of) role of the PI3K/Akt on the regulation of HIF by oxygen Next, we focused on the identification of novel HIF-target genes by the computational prediction of HIF-binding sites. Our first work on this direction led us to the identification the long-sought hypoxia-response element on EGLN3, a gene encoding for an oxygen-sensor (https://www.ncbi.nlm.nih.gov/pubmed/15823097). It is worth mentioning that we approach most of our research projects by a combination of computational and experimental techniques, an strategy that has allowed us to tackle old problems, such as identification of HIF-target genes, from novel angles (https://www.ncbi.nlm.nih.gov/pubmed/20061373). To to gain further training on computational biology, I spend a year (2011-2012) as a vissiting professor at the University of British Columbia working in the laboratory of Dr. Wyeth Wasserman, a world leading expert on bioinformatics approaches to study transcription factors. Since then, we use a blend of web lab and in silico approaches to continue exploring the regulation of transcription by hypoxia and its role on human disease. In this regard, we are currently interested in understanding how genetic variation in HIF binding regions affect the transcriptional response to hypoxia and its role in disease progression (https://www.ncbi.nlm.nih.gov/pubmed/27625398).
Finally, my position as associate professor includes research and teaching responsibilities. I find both activities complementary and equally rewarding. Accordingly, I have also participated in projects trying to improve our teaching methodologies (https://www.ncbi.nlm.nih.gov/pubmed/23483652). I currently teach undergraduate courses on “Bioinformatics and Systems Biology” and “Programming Tools for Biochemistry and Molecular Biology” and graduate courses on “Applied Statistics” and “Regulation of Gene Expression”
TÍTULO: “Diseño de un SPOC para la adecuación de conocimientos de Expresión Génica. Valoración de su impacto.”
ORGANISMO: Proyectos Innovación Docente UAM 2015-2016.
COORDINADOR: Luis del Peso.
TÍTULO: “Evaluación de las estrategias de innovación docente implantadas para la adaptación al EEES de la asignatura Metabolismo (18427) perteneciente al Grado en Nutrición Humana y Dietética”.
ORGANISMO: Proyectos para el Desarrollo de las Enseñanzas UAM 2012.
COORDINADOR: Luis del Peso.
TÍTULO: “Implantación y difusión de las titulaciones de Posgrado: Máster en Biología Molecular y Celular, Máster en Biomedicina Molecular y Máster en Biotecnología”.
ORGANISMO: Convocatoria de Proyectos de Convergencia Europea en la UAM.
Dotación: 10500 euros.
COORDINADOR: Javier Diaz Nido
The evolution of life on Earth was dramatically affected by the fluctuations on the concentration of a simple molecule, oxygen (O2). This gas was generated as a by-product of the first photosynthetic organisms that lived some some 3500 million years ago and soon (in geological terms!) after the “discovery” of photosynthesis free oxygen began to build-up in the atmosphere. As oxidative metabolism is more efficient than anaerobic pathways, presence of oxygen may have facilitated the development of large and complex animals. However, the new opportunities provided by oxygen came with new challenges. Most animal tissues are extremely dependent on a continuous supply of oxygen to support their high metabolic demands so that oxygen deprivation, even for a brief period, leads to irreversible damage or death. This is clearly manifest in several human diseases including myocardial infarction, stroke and cerebral palsy among many others. On the other hand, the use of oxygen as acceptor of electrons increases the risk of reactive oxygen species (ROS) production. As implied by its name ROS are extremely reactive molecules that can damage cell structures and macromolecules. The cumulative damage produced by ROS is called oxidative stress and increasing evidence suggest it contributes to aging and degenerative diseases. Thus, it is not surprising that all metazoan cells share an evolutionarily conserved molecular machinery that continuously monitor oxygen levels. When oxygen supply is not sufficient to meet the cellular needs, a condition termed hypoxia, cells activate a transcriptional response that aims to restore oxygen supply while limiting its consumption and the generation of ROS. Importantly, this response is induced in a large number of pathologies of high prevalence including cardiorespiratory diseases and cancer. Thus, better understanding of this cellular response could potentially help improve the clinical management of these diseases.
The elucidation of the cellular and molecular responses to hypoxia constitutes an important research topic due to the central importance of this process in cellular physiology and its involvement in high-incidence pathologies such as cardiovascular/respiratory diseases and cancer. The Hypoxia Inducible Transcription Factor (HIF) plays a pivotal role in this response by controlling the expression of most of the genes involved in the adaptation to hypoxia. Our research group aims to contribute to the understanding of the transcriptional response to hypoxia and to exploit this knowledge to improve clinical management of pathologies in which development of tissue hypoxia is a common feature. Specifically, the current goals of our research team are:
To achieve these goals we use a combination experimental and computational approaches and employ a of wide array of experimental models with primary human endothelial cells being a central paradigm in our research. As our primary interest is understanding how oxygen regulates gene expression at a global scale, we make extensive use of genomic and transcriptomic techniques including RNA-seq, ChIP-seq and targeted-genome sequencing among others. We analyze the experimental data generated by these techiques and integrate it with the wealth of publicly available datasets to generate data-driven hypothesis. Finally, test these hypothesis in vitro using cell and in vivo by means of a variety of cell and molecular biology techniques including genome editing.
Nov_2015- Miembro Claustro UAM en representación de Profesores Doctores con Vinculación Permanente.
Ene_2016- Miembro Junta Facultad (Medicina) en representación Profesores Permanentes.
Oct_2012- Miembro Comisión Grado Bioquímica.
Jul_2013- Coordinador 4º curso del Grado en Bioquímica.
Dic_2007-Dic_2010 Secretario Departamento Bioquímica.
María Tiana Cerrolaza (Investigadora Predoctoral).
Rosana Hernández Sierra (Técnico Laboratorio, compartido).
Daniel Martínez Alcazar (Estudiante TFM).
Clara Galiana (Estudiante TFG).
Salvador Naranjo (Feb 2006) “Regulation of Hypoxia Inducible Transcription Factor 2 by NGF and effect of hypoxia on PC12 cells viability”. Cum Laude.
Yolanda Cuevas (May 2006) “Development of a conditional replicative adenovirus (Ad-9XHRE1A) targeting tumors with active HIF pathway. Antitumoral efficacy against VHL-defficient clear cell renal carcinomas” Cum Laude.
Nuria Pescador (Mayo 2007) “Identification of cis-elements responsible for gene expression regulation in response to hypoxia Inducible Factors.” Cum Laude.
María Luisa Alcaide (Jun 2009) “Generation of a yeast system to study the regulation of the mammalian Hypoxia Inducible Factor. Optimization to identify small molecules affecting HIF prolyl hydroxylases activity” Cum Laude.
Diego Villar (Feb 2010) “The role of binding selectivity in the HIF pathway: biochemical identification of a substrate binding region in HIF prolyl hydroxylases and in silico prediction of ancillary sequences contributing to HIF DNA binding selectivity” Cum Laude, European Thesis.
Amaya Ortiz (Sep 2010) “A computational approach for the identification of novel Hypoxia Inducible Factor target genes”. Cum Laude.
Laura Gomez (Dic 2013) ”Regulation of EFNA3 expression by hypoxia through a novel lncRNA-mediated mechanism. A potential role in cancer metastasis” Cum Laude, European Thesis.
Laura Deguiz (Dic 2015) “Identification of non-coding genetic variants in samples from hypoxemic respiratory disease patients that affect the transcriptional response to hypoxia.” Cum Laude.
María Tiana (Ene 2016)” Characterization of the molecular machinery responsible for gene downregulation during hypoxia by a combination of computational and experimental tools” Cum Laude, European Thesis.
Beatriz Ranz (Jun 2014). “Computational Prediction of HIF binding Sites”.