Image Credit: Belle Creith, Sumeet Mahajan and Claire Clarkin
Project No. 2410
PRIORITY STANDARD PROJECT
Primary Supervisor
Dr Claire Clarkin – University of Southampton
Co-Supervisor(s)
Dr Kathrine Williams – University of Portsmouth
Dr Valentina Cardo – University of Southampton
Dr Owen Rackham – University of Southampton
Summary
The post-pubertal skeleton exhibits sexual dimorphism and becomes anatomically and physiologically distinct in mammalian species.
In women, sex differences are amplified with age and in the onset of degenerative skeletal pathologies such as post menopausal osteoporosis. Traditionally, the imbalance in disease rates between females and males has been attributed to altered levels of circulating sex hormones. However, there is evidence that the genetic differences in male and female cells result in differences in bone properties, including microstructure and shape, which contribute to sexual dimorphism between males and females. (1,2)
Hormone independent sex-specific mechanisms could now be exploited to develop drug treatments for bone disease and fracture repair between sexes and across the non-binary gender spectrum. Gender is known to produce substantial health inequalities with some skeletal disease more prevalent in women than men. Further, transgender individuals also suffer significant health disparities in multiple arenas (3, 4). It has been demonstrated previously that it is possible to switch the phenotype of one cell type to another where ‘epigenetic rewiring’ of specific cells can be reversed by targeting transcription factors (TFs) (8). Mogrify is a novel computational prediction tool which requires which requires only gene expression data to predict TFs or their combinations for cell conversions (9). Whether sex-specific TFs exist are present in skeletal cell populations to underlie the sex specific bone cell behaviour and function we have previously described remains uninvestigated.
This cross-disciplinary studentship will combine cell biology and computational approaches to understand if the underlying genetics of sex differences in skeletal cells are distinct and/or predictive. In vitro models of trans gender effects will also be incorporated into this model to investigate whether this genetic programming is reversible with sex hormoness. Revealing novel gender-specific genetic mechanisms underlying bone health could enable personalised treatments and technologies to be developed across the gender spectrum.
1. Goring, A., Sharma, A., Javaheri, B., Kanczler, J., Mahajan, S., Hesse, E., Clarkin, CE. (2019). Regulation of the bone vascular network is sexually dimorphic. Journal of Bone and Mineral Research. DOI: 10.1002/jbmr.3825.
2. Sharma A, Goring A, Johnson P, Emery R, Hesse E, Olsen B, Boyde A , Pitsillides AA, Oreffo R, Mahajan S and Clarkin CE (2021) Molecular imaging at the multiscale discloses sexually dimorphic control of collagen organisation in bone pathology. Disease Models and Mechanisms, 14(3), [dmm048116]. https://doi.org/10.1242/dmm.048116
3. Bradford J, Reisner SL, Honnold JA, Xavier J. Experiences of transgender-related discrimination and implications for health: Results from the Virginia transgender health initiative study. American Journal of Public Health. 2013;103:1820–1829.
4. Bauer GR, Hammond R, Travers R, Kaay M, Hohenadel KM, Boyce M. I don’t think this is theoretical’; this is our lives: How erasure impacts health care for transgender people. Journal of the Association of Nurses in AIDS Care. 2009;20:348–361.
5. Khwaja A, Bjorkholm M, Gale RE, Levine RL, Jordan CT, Ehninger, G et al (2016) l Acute myeloid leukaemia. Nat Rev Dis Prim 2:16010
6. Lee Lin Ming Christodoulou Eleni G , Shyamsunder Pavithra , Chen Bei Jun, Lee Kian Leong, Fung Tsz Kan , Eric So Chi Wai, Wong Gee Chuan , Petretto Enrico , Rackham Owen J L Ong S Tiong A novel network pharmacology approach for leukaemia differentiation therapy using Mogrify® (2022) Oncogene doi: 10.1038/s41388-022-02505-5. Epub 2022 Oct 21.