PhD Studentship: Find-me and eat me: understanding how signals from dying cells control and subvert macrophage behaviour

University of Sheffield - Department of Infection, Immunity and Cardiovascular Disease (IICD), The Medical School

Billions of cells undergo apoptosis (programmed cell death) on a daily basis, and this process is fundamental to development, homeostasis and how we deal with infection and inflammation [1]. Suppression of apoptosis is a key step in cancer progression, while pathogens often inhibit this process as part of their pathology. Normally, phagocytic cells such as macrophages detect signals released by dying cells (‘find-me’ cues) and then subsequently engulf and degrade these apoptotic cells. This is an important clearance mechanism and failures in this process can contribute to the development of pathologies such as chronic inflammatory disease, atherosclerosis and damaging autoimmune conditions; thus greater understanding of the regulation of apoptotic cell clearance has relevance to a broad range of human diseases.

This project employs a 2-pronged approach to understand how signals from dying cells impact macrophage behaviour: we will use the highly genetically-tractable organism Drosophila melanogaster (the fruit fly) to identify novel regulators of this apoptotic cell detection by macrophages [2]; in parallel we will examine how human macrophages migrate in response to novel cues found in Drosophila and other apoptotic cell find-me cues previously identified. We will challenge macrophages with competing gradients of cues (apoptotic-derived vs other chemokines) in microfluidic chambers to understand how the signalling is integrated.

Therefore this project aims to:

  • identify the signals that fruit fly macrophages use to track down apoptotic cells in vivo
  • translate those findings to vertebrate tissue culture chemotaxis models
  • understand the signalling basis that underlies competition between apoptotic cell find-me cues and other signals involved in innate immune cell migratory responses

A combination of pharmacological and genetic approaches will be used; where human homologues exist we will knock these genes down in primary human macrophages and test their role in migration towards apoptotic cells and apoptotic cell clearance in vitro. Since it is known that phagocytosis of apoptotic cells is impaired in chronic lung inflammation [3], we will examine whether persistent stimulation with the find-me cues identified in this proposal impairs apoptotic cell clearance by macrophages. We will also isolate macrophages from patients with chronic obstructive pulmonary disease (COPD) and determine if modulation of the signalling pathways identified in this proposal can correct defects in phagocytosis.

Therefore this work will not only identify novel regulators of a process central to human health, but also provide an insight into mechanisms that underpin a range of disease conditions, generating new targets for the development of immunomodulatory therapies.

The Faculty of Medicine, Dentistry & Health Doctoral Academy Scholarships cover Home/EU fee and RCUK rate stipend for three years. Overseas students may apply but will need to fund the difference between the Home and Overseas fee from another source.

Proposed start date: October 2017

References

[1] Arandjelovic S and Ravichandran KS (2015). Nature Immunology. 16(9):907-17.

[2] Weavers H, Evans IR, Martin P & Wood W (2016). Cell. 165(7):1658-71.

[3] McCubbrey BS and Curtis JL (2013). Chest. 143(6): 1750–1757.

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Type / Role:

PhD

Location(s):

Northern England