Oxygen homeostasis, central to physiology, is altered in high-incidence pathologies such as cardiovascular diseases and cancer. Therefore, the elucidation of cellular and molecular adaptive responses to hypoxia is an important topic of biomedical research. The Hypoxia Inducible Transcription Factors (HIFs) play a pivotal role in this response by controlling the expression of most of the genes involved in the adaptation to hypoxia. The aim of our group is to contribute to the understanding of the transcriptional response to hypoxia and the cellular and molecular mechanisms underlying central adaptation responses like angiogenesis. Our long-term goal is to exploit this knowledge to improve the clinical management of pathologies in which the development of tissue hypoxia is a common feature. Within this framework we are currently working on several specific lines of research as detailed below:
Characterization of the molecular mechanisms responsible for the transcriptional response to hypoxia
Despite great progress in this area, many aspects remain to be clarified. Among them, what determinants are used by the different members of the HIF family to identify their target genes and how HIF represses the expression of genes in response to hypoxia. It is also unknown how variant gene expression patterns occur over time of exposure to hypoxia, while HIF levels remain relatively constant. In addition to advancing our understanding of this pathway, the answer to these questions could lead to the identification of new therapeutic targets.
Identification of polymorphisms affecting HIF binding sites and characterization of their functional impact
Most of the human genetic variation lies in non-coding regions of the genome, but its functional impact in phenotype and disease is almost unknown. Although several common SNPs that affect the transcriptional response to hypoxia have been identified, a global analysis of common genetic variability on the response to hypoxia and its impact on phenotypic variability is still lacking. The identification of the effects of genomic variability is a key step paving the way to precision medicine.
Cellular and molecular mechanism of angiogenesis regulation by hypoxia
One of the paradigmatic adaptive responses to hypoxia is the activation of biological processes that aim to increase oxygen supply to tissues. Angiogenesis is the main mechanism that allows vascular expansion and a fundamental adaptive response to hypoxia in physiology and disease. Despite the central role of HIFs in the induction of angiogenesis, a detailed knowledge of how HIFs regulate the complex process of angiogenesis is still incomplete. Specifically, how HIF regulates the balance between proliferation and differentiation and which HIF-targets play a role in this equilibrium needs to be clarified.
Regulation of metabolism by hypoxia and role of HIF in metabolic diseases
A complementary response to the increase in oxygen supply is the reprogramming of cell metabolism to reduce oxygen consumption while maintaining energy generation. Several important aspects of how hypoxia regulates metabolism remain poorly understood. Specifically, neither the mechanism by which hypoxia regulates lipid metabolism nor its role in the adaptation to hypoxia are well understood. Given the role of metabolic alterations in cardiovascular disease and cancer, a better understanding the metabolic reprogramming by hypoxia could help improve the management of these pathologies.