Illuminating molecular circuits in oxygen homeostasis
- Reference number
- FFL24-0175
- Project leader
- Kragesteen, Bjørt Katrinardóttir
- Start and end dates
- 250801-300731
- Amount granted
- 15 000 000 SEK
- Administrative organization
- Karolinska Institutet
- Research area
- Life Sciences
Summary
In recent human evolutionary history, migrations around the globe have led to a multitude of environmental challenges such as new pathogens, diets, and high-altitude hypoxia. Remarkable examples of human genetic adaptation and increased fitness provides a natural experiment which can studied to understand the underlying molecular, cellular and systems principles that regulate fundamental biological processes such as oxygen homeostasis critical to medically relevant hypoxia. As an incoming independent group leader at MBB at Karolinska Institutet, I will develop an experimental approach whereby human evolutionary genomics is brought to life in multicellular organoids and high-throughput approaches are used to map and decipher regulatory networks. In this SSF-project, we will use the adaptation of Tibetans to living in high altitude hypoxic environment and investigate their protective physiological changes including cardiopulmonary function and erythropoiesis central to physiological oxygen homeostasis. The objectives of the project are: 1) Identify the critical cells and molecular circuits underlying systemic oxygen sensing and response in hypoxia; 2) Decipher the molecular mechanism of Tibetan adaptation to high altitude hypoxia. Together, this approach will reveal the intricate interplay between the genome, epigenome, and physiology, to illuminate the mechanisms of oxygen homeostasis that opens new avenues to understanding human health disparities.
Popular science description
Lifegiving oxygen is fundamental to the function and survival of most life form on Earth by sustaining essential biochemical reactions. In air-breathing organisms, oxygen is extracted from the air through the lungs where it binds to red blood cells that carry the oxygen to all cells and tissues in the body. Failure of meeting the body’s unceasing demand for oxygen leads to hypoxia and can produce life threatening events causing cells and tissue damage and even death. Strikingly, some human populations have evolved an increased resistance to hypoxic environments. This includes Tibetans that have lived at high altitude hypoxia. This low oxygen environment poses extreme challenges to human physiology, yetTibetans have genetically adapted and show increased fitness compared to non-adapted neighbours. Investigating this natural experiment can thus shed light onto fundamental mechanisms regulating biological processes that control oxygen homeostasis. But how does the body ensure this systemic oxygen supply and what happens when there is a lack of oxygen? A few specialised systems exist throughout the body, for example the carotid body that sits on top of the carotid arteries in the neck can sense any changes in systemic oxygen availability and in turn increases breathing and heart rate. Another response is the increase the number of red blood cells circulating to increase the oxygen transportations. Yet, the precise underlying molecular mechanisms of how these cellular systems sense and control oxygen homeostasis in unknown. My lab will use mouse and advanced 3D human in vitro models to mimic high altitude hypoxia and map and perturb the cellular responses using molecular technologies that detect transcriptional (mRNA) and epigentic changes at single cell resolution. This innovative interdisciplinary approach will illuminate fundamental principle of oxygen homeostasis. New insights may shed light on medically relevant hypoxia and the next generation of regenerative medicinal approaches to better human health.