Detalle de: Hypoxia and Angiogenesis

What is hypoxia and why do we care?

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.

Goals of our research team

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:

1. Characterization of the transcriptional response to hypoxia. Including identification of the molecular mechanism responsible for gene downregulation during hypoxia and characterizacion of the gene regulatory network involving HIFs.
2. Understanding the role of HIFs in endothelial cells in the process of angiogenesis.
3. Identification of polymorphisms affecting HIF binding sites and characterization of their contribution to disease inter-individual variability in cancer and cardiopulmonary diseases.

Our approach

1. 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.