Our research interests are extremely broad. This is because respiratory, cardiovascular and metabolic function are all intimately linked, and there is an important interplay between the detailed understanding of parts of these systems and an understanding of the integrated whole. We have a particular interest in exercise, because exercise provides the greatest single stress on these systems in most normal circumstances. We also have a particular interest in the roles of carbon dioxide and oxygen in these processes, because they are the principal gases exchanged by the lungs and because they play such a central role in the regulation of both the respiratory and cardiovascular systems.

Central to the work of our group has been the technique of dynamic end-tidal forcing. This technique enables the levels of carbon dioxide and oxygen in the arterial blood to be set irrespective of any changes in metabolism or ventilation of the lungs. We have used this technique extensively to provide quantitative descriptions, through the use of mathematical models, of the dynamic responses of the lungs and the blood vessels to variations in the levels of carbon dioxide and oxygen in the blood.

As an extension of the technique of dynamic end-tidal forcing, our group developed a chamber in which the levels of carbon dioxide and oxygen in the arterial blood could be maintained constant for many hours/days. This enabled us to study, under very controlled conditions, the slower responses to low oxygen (the so called acclimatization responses to hypoxia) that occur when individuals travel to high altitude. Using this approach, we were able to show that respiratory (or ventilatory) acclimatization to hypoxia did not arise through mechanisms involving changes in the acidity of the body fluids as had been previously thought, but rather as a direct consequence of the low oxygen itself.

Over the past decade or so, a very important advance has been the discovery of the family of transcription factors known as hypoxia-inducible factors (HIF) that regulate gene expression in response to cellular hypoxia. Much of our current research is now focussed on trying to gain an understanding of the role of HIF in the integrative responses of the cardiovascular and respiratory systems to sustained hypoxia in humans. Towards this aim, we have complemented our integrative studies of human function with experimental work on genetically-modified mice with specific alterations within the HIF system; with molecular studies of human cellular responses to hypoxia – which we aim to relate through to integrative function; and with studies of the genetic adaptation of the world’s high-altitude populations to the low oxygen of their environment. We also have a developing programme of work in relation to iron because the biology of hypoxia and the biology of iron deficiency are intimately linked at both the molecular and cellular level.

Much of the work within our group is undertaken by graduate students working towards a doctorate. In many cases, these students are jointly supervised with other colleagues in the Department, which adds breadth to their research training. The laboratory has an international feel with students coming from many different countries . Recent students have been funded through Rhodes Scholarships, Marshall Scholarships, Felix Scholarships, Clarendon Bursaries, ORS awards, as well as through funding arising from their native country.

Current Research Programme

Some specific topics that are currently being addressed in our laboratory are as follows:

Genetics of hypoxia and of high-altitude populations.

Recently, we identified the first specific human gene locus that had undergone natural selection in an indigenous high-altitude population (Tibetans). Other loci have now also been described. Our current work in this area is directed towards identifying the functional variants that underlie this selection. It is also directed towards studying other high-altitude populations, including animal populations, to try to identify other sites within the genome that have undergone natural selection. Finally, it is also directed towards identifying human variants that either predispose or protect an individual in relation to disorders of high altitude.

Iron status and hypoxia.

The cellular and molecular responses to hypoxia and to iron deficiency are intimately linked, and we have shown, for example, that the progressive increase in pulmonary arterial pressure on exposure to hypoxia is mimicked by iron chelation. Furthermore, iron loading seems to protect against some of the deleterious effects of exposure to hypoxia. We now have a programme of work to explore the interactions between iron and hypoxia and their effects on integrated physiological function (including exercise capacity) in both humans and in mice.

Ventilatory acclimatization to hypoxia and hypoxia-inducible factor.

A number of lines of evidence suggest that hypoxia-inducible factor plays an important role in ventilatory acclimatization to altitude. However, the mechanisms by which it does this are unknown. This project is exploring the effects on breathing and the effects on the carotid body of a number of potentially informative genetic modifications of the hypoxia-inducible factor pathway. We are also exploring the effects of novel pharmacological agents targeting the hypoxia-inducible factor signalling pathway.

New technologies for determining gas exchange.

Inventing new technologies for respiratory research in humans has always been an interest of our group. Currently, we are working on novel ways of sensing respired gas concentrations using lasers that will allow the measurements to take place directly within the main gas stream. This has important advantages for calculating metabolic exchange, because the absence of delay and the instrument’s very fast dynamic allows the measurements of flow and composition to be aligned accurately.

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Peter Robbins