Background: Inflammation is a response of the innate immune system that controls infection and promotes resistance and tissue repair. However, inflammation in the absence of infection, during injury or disease, is often damaging, and is increasingly implicated as a causal factor in many diseases. In this context, inflammation is a maladaptive response and thus an attractive therapeutic target. Understanding the regulation of inflammation during disease processes could lead to the identification of new therapeutic targets for the treatment of devastating conditions. Inflammatory cytokines associated with damaging inflammation include pro-inflammatory members of the interleukin-1 (IL-1) family, namely IL-1α and IL-1β. The recent CANTOS trial has further confirmed the IL-1β pathway as important with respect to major non-communicable diseases. In contrast, the biology and therapeutic potential of targeting IL-1α is relatively poorly explored. However, in a murine model of sepsis in neonates lethality is dependent specifically on IL-1α. According to the NHS sepsis kills at least 46,000 people per year in the U.K. alone (www.nhs.uk/conditions/sepsis/). There is also growing evidence for a role for IL-1α in cellular senescence and cancer, and we have discovered an important role for IL-1α in ischaemic brain injury. Thus IL-1α is a protein of considerable biomedical importance.
We have exciting preliminary data suggesting that the activity of IL-1α is uniquely regulated by its pro-domain. Thus understanding the regulation of IL-1α has significant biological and biomedical implications. Here we propose a PhD project building upon these exciting data to make a step change in how we understand the regulation of IL-1α, and thus to make new insights into the regulation of inflammation in general.
Objectives: This PhD proposal addresses three specific related questions each supported by new preliminary data. The overall objective is to understand the regulation of IL-1α. Our previous research has identified that IL-1α can traffic to the nucleus in microglia (macrophage-like cells in the brain), and that this is regulated during acute brain injury such as stroke. Given IL-1α is known to exacerbate brain injury understanding its regulation is of high importance. Specifically, important questions the proposal will address are:
1) How does the pro-domain of IL-1α affect its trafficking?
2) How does the pro-domain affect the cleavage of pro-IL-1α?
3) How does brain injury affect trafficking and processing of IL-1α?
Training: The student will be trained in molecular (cloning) and cell biology (live cell confocal microscopy), in vivo biology, in addition to a suite of biochemical and immunological methods (e.g. immunocytochemistry, western blotting, immunoprecipitation) that are well established in the supervisors labs and within the Faculty. Additional training will be provided as needed. In addition to acquiring a comprehensive set of contemporary lab skills the applicant will participate in public engagement events learning effective communication skills.
Outcomes: The work arising from this project will lead to several anticipated outcomes:
- Improved understanding of fundamental biological processes
- Student training and development
- Engagement with communities in Manchester
- Substantive external funding application
- Scientific publications suitable for REF
- Identification of potentially therapeutic avenues of research https://www.research.manchester.ac.uk/portal/David.Brough.html https://www.research.manchester.ac.uk/portal/stuart.allan.html https://www.research.manchester.ac.uk/portal/martin.lowe.html
Applications are invited from UK/EU nationals only. Applicants must have obtained, or be about to obtain, at least an upper second class honours degree (or equivalent) in a relevant subject.