Sex dimorphisms in macrophage function, inflammatory pathology and ageing

Supervisors: Dr Jennifer Regan, Dr Steve Jenkins

Project Description:

Ageing is the largest risk factor for the developed world's biggest killers, and the impact of age-related disease is one of society’s foremost challenges. Men and women do not age in the same way: women live longer than men, and the sexes suffer from age-related diseases at a different rate (1). Defective immunity is implicated as both cause and effect of ageing. For example, inflammation is an essential response to wounding and infection, but when inflammation is misdirected, or chronic, tissues damage ensues and development of age-related disease is accelerated.

It has long been known that men and women have a different propensity toward infectious and auto-inflammatory diseases. In part, this is due to sex dimorphisms in the function of innate immune cells such as macrophages. However, the molecular regulation and cell behaviour underlying these dimorphisms is not well-understood. Ex vivo studies of macrophages point to differences between men and women, but these studies by their nature cannot reveal how these cells behave inside the body, and over age, to impact pathology and lifespan.

We use a Drosophila model to tackle complex and key issues of the reciprocal interactions of sex, innate immunity and ageing. To do this we use several methodological approaches, including confocal and light sheet in vivo microscopy, infection studies, demographic analysis, genetics and transcriptomics. We have recently shown that macrophages require activation by a steroid hormone (2), and that age-related gut pathology and lifespan are sexually dimorphic (3). This PhD will build on this work to uncover the role for macrophage sex in ageing of males and females.

Project aims include:
(i)    compare inflammatory dynamics of macrophages in males and females in vivo;
(ii)    identify conserved molecular regulators of sex-specific macrophage function using next-generation transcriptomics in Drosophila and mouse models;
(iii)    uncover the role for macrophage sex in sexually dimorphic, age-related inflammatory pathologies and lifespan.

1.    Regan, J. C., & Partridge, L. (2013). Gender and longevity: why do men die earlier than women? Comparative and experimental evidence. Best practice & research Clinical endocrinology & metabolism, 27(4), 467-479.
2.    Regan, J. C., et al (2013). Steroid hormone signaling is essential to regulate innate immune cells and fight bacterial infection in Drosophila. PLoS pathogens, 9(10), e1003720.
3.    Regan, J. C., et al (2016). Sex difference in pathology of the ageing gut mediates the greater response of female lifespan to dietary restriction. Elife, 5, e10956.

If you wish to apply for this project, please go to this link.