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Title: The role of the HIF-PHD pathway in carotid body Type I cell proliferation
Author: Fielding, James
ISNI:       0000 0004 8503 5228
Awarding Body: University of Oxford
Current Institution: University of Oxford
Date of Award: 2019
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The carotid body is an important peripheral chemoreceptor in adult mammalian physiology. A small, paired neuroendocrine tissue located at the carotid bifurcation in the neck, the carotid body is a polymodal chemoreceptor which detects fluctuations of a number of substances in arterial blood, most notably oxygen. In response to low oxygen levels (hypoxia), the Type I cells of the carotid body release neurotransmitters onto afferent nerves to stimulate a rapid adaptive hyperventilatory response. In addition to this acute response, sustained hypoxia results in a substantial increase in the size of the carotid body, known as carotid body hyperplasia. It has been proposed that this proliferative response qualifies the carotid body as a stem cell niche, and characterizing the mechanisms behind this proliferation is of significance for understanding both the specialist function of the carotid body and the wider influence of hypoxia on cellular proliferation. Previous work in this field has implicated the hypoxia-inducible factor (HIF) transcription factors and the regulatory prolyl hydroxylase family (PHD) as master regulators of the responses to hypoxia across the organism, and in the carotid body specifically. This thesis also establishes that pseudohypoxic stimulation of the carotid body Type I cells via genetic inactivation of the HIF prolyl hydroxylase PHD2 is sufficient to drive a multilineage expansion of the carotid body. The resulting pseudohypoxic carotid bodies were grossly enlarged, highly vascular and contained multiple ultrastructural abnormalities. An exciting implication of this is that this mouse line may represent the first mouse model for carotid paraganglioma, a subtype of paraganglioma derived from the carotid body. In addition to the effects on proliferation, ultrastructural changes were observed in the signalling vesicles of the Type I cells, suggesting a functional link between the HIF-PHD pathway and the acute signalling function of the organ. Taken together, these results demonstrate an essential role for the HIF-2α-PHD2 couple in the function of Type I cells in the carotid body.
Supervisor: Bishop, Tammie ; Ratcliffe, Peter Sponsor: Ludwig Cancer Research
Qualification Name: Thesis (Ph.D.) Qualification Level: Doctoral
EThOS ID:  DOI: Not available
Keywords: Medicine ; physiology