HIF prolyl 4-hydroxylases and transmembrane prolyl 4-hydroxylase – The effects on a mouse model of human multiple sclerosis and skin development

Thesis event information

Date and time of the thesis defence

Topic of the dissertation

HIF prolyl 4-hydroxylases and transmembrane prolyl 4-hydroxylase – The effects on a mouse model of human multiple sclerosis and skin development

Doctoral candidate

Medical Doctor Mia Monnius

Faculty and unit

University of Oulu Graduate School, Faculty of Biochemistry and Molecular Medicine, ECM and Hypoxia

Subject of study

Medicine

Opponent

Professor Eoin Cummins, UCD Conway Institute, University College Dublin, Ireland

Custos

Docent Joni Mäki, University of Oulu, Faculty of Biochemistry and Molecular Medicine

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The effects of cellular oxygen sensors on a mouse model of human multiple sclerosis and skin development

Inactivation of HIF-P4H-1 enzyme may be a potential therapeutic intervention as an alternative treatment of multiple sclerosis (MS) in the future, as this was observed in a mouse model of MS. Inactivation of HIF-P4H-3 does not have an effect on the mouse model of MS, whereas inactivation of P4H-TM should be avoided as this aggravates the MS model. HIF-P4H-2 in turn has an essential role in hair growth.

Multiple sclerosis (MS) is the most prevalent chronic neurological disease of young adults worldwide, leading to pathological changes in the central nervous system, patient disability and death. The prevalence of MS is increasing especially in Nordic countries, including Finland. The management of MS is challenging due to the heterogeneity of patient symptoms, the exact causes behind MS still not fully being understood, and furthermore, the complications of higher doses of the current most effective drugs are reported to be severe. Therefore, it remains crucial to generate novel drugs for MS symptom management and for fighting the disease progression. Several of the current drugs against MS disease today have been generated using the MS mouse model that was used in this thesis work.
Cells are able to sense the fluctuation of oxygen levels, which is vital for the normal function, growth and development of tissues. HIF prolyl 4-hydroxylases 1-3 (HIF-P4Hs 1-3) are the oxygen sensors of cells that control the stability of hypoxia-inducible transcription factors (HIFs) under normal oxygen levels (normoxia) and lowered oxygen levels (hypoxia). HIFs in turn control the gene expression of hundreds of genes under hypoxia. Therefore, in hypoxia, gene expression shifts to another direction from that occuring in normoxia and aims for organism to be able to compensate for the low oxygen availability. This has been shown to significantly affect the function of immune system as well. HIF-P4H inhibitors have recently been taken into use in clinical practice for the treatment of renal anaemia, which has led to growing interest in investigating their suitability as treatments against other clinical conditions too, such as inflammatory diseases. Prolyl 4-hydroxylase transmembrane protein (P4H-TM) is another P4H enzyme. Unlike the HIF-P4Hs, P4H-TM is a transmembrane protein located in the endoplasmic reticulum membrane. The exact roles of P4H-TM have still not been elucidated; however, current evidence demonstrates that P4H-TM is central for the function of the central nervous system.
This thesis work examined for the first time in the world the effects of HIF-P4H-1, -3 or P4H-TM inactivation on a mouse model of MS. The results in the first part of the thesis indicated a significant ameliorating effect on the course and tissue inflammation of the MS mouse model after HIF-P4H-1 deletion, but not after HIF-P4H-3 deletion. When HIF-P4H-1 was depleted, the onset of symptoms was delayed and the severeity of the clinical signs was ameliorated. Additionally, the spinal cords had significantly less inflammatory changes. Therefore, silencing HIF-P4H-1 may be a potential therapeutic intervention as an alternative treatment of MS in the future. In contrary, inactivation of P4H-TM led to significantly aggravated disease. The results of the second part of this thesis work give novel insights into the inactivation of P4H-TM in the context of MS mouse model and demonstrate that inactivation of P4H-TM should be avoided when developing HIF-P4H inhibitors as potential drugs for MS.
In the third study of this thesis work, a novel role of HIF-P4H-2 in the regulation of hair growth is presented. A mouse model where HIF-P4H-2 is conditionally inactivated in Forkhead box D1 (FoxD1)-lineage mesodermal cells was generated. This had a significant effect on hair follicle development, as the interplay between the hair follicle dermal papilla cells and keratinocytes was disrupted. On tissue level, instead of normal hair follicles and hair, keratin-filled cysts were formed, which led to alopecia. Alopecia is common amongst humans and this study of this thesis demonstrates that HIF-P4H-2 function is essential for normal hair growth.
Last updated: 13.10.2022