The nuclear membrane is more than a passive barrier that separates the nucleus from the cytoplasm; it is a dynamic signalling hub that integrates mechanical, transcriptional, and immune-regulatory cues. Structurally, the nuclear membrane consists of an inner and outer bilayer connected at nuclear pores, underpinned by the nuclear lamina which is composed of intermediate filament proteins such as lamins. Beyond providing structural support, the nuclear membrane is now recognised as a key regulator of chromatin organisation, transcriptional accessibility, and communication between the nucleus and cytoplasm. These features place the nuclear membrane in a central position to modulate cellular responses to stress and inflammatory stimuli.
A growing body of work shows that the nuclear membrane actively shapes inflammatory signalling. For example, nuclear pore complexes control nucleocytoplasmic transport (NCT) of proteins, including transcription factors such as NF-κB, a master regulator of pro-inflammatory gene expression. NFkB is usually localised in the cytoplasm in immune cells, but translocates to the nucleus following inflammatory stimuli where it increases expression of genes involved in several different pro-inflammatory response pathways. Recent research showed that lamin A, a key structural protein in the nuclear lamina, is degraded following LPS treatment (lipopolysaccharide – a bacterial protein used experimentally to stimulate a pro-inflammatory response) in macrophages. Furthermore, increased nuclear translocation of NFkB was observed in lamin A knockout macrophages, indicating that structural components of the nuclear membrane play a role in the regulation of inflammations. However, the mechanisms underlying this are poorly understood. It is also unknown whether other components of the nuclear membrane are involved in regulation of inflammation, or whether lamin A loss also enhances NCT of other proteins, including other pro-inflammatory transcription factors. The downstream impact of lamin A knockout on inflammatory signalling pathways such as inflammasome activation and interferon response has also not been characterised. This project will address these important gaps in current knowledge. Understanding how inflammation is controlled at a fundamental level is of broad biological importance. Inflammation is essential for host defence and tissue repair, but must be tightly regulated to avoid chronic activation, which can damage cells and tissues.
In addition, we will investigate how the processes described above are affected by healthy ageing. With age, immune responses undergo characteristic changes described as “inflammageing”; a persistent, low-grade pro-inflammatory state that contributes to frailty, impaired tissue function, and increased risk of age-related conditions. Despite its importance, the mechanisms that drive inflammageing remain incompletely understood. There is also evidence that nuclear membrane dynamics change during healthy ageing, and therefore we hypothesise that changes in the nuclear membrane and NCT contribute to inflammageing.
Entry Requirements
Applicants should hold (or be about to obtain) a First or Upper Second class (2:1) UK honours degree, or international equivalent, in a relevant subject.
Application Guidance
Candidates must contact the primary supervisor before applying to discuss their interest in the project and assess their suitability.
Apply directly via this link: https://tinyurl.com/zycedema or on the online application portal, select BBSRC DTP PhD as the programme of study. You may apply for up to two projects within this scheme. To do so, submit a single online application listing both project titles and the names of both main supervisors in the relevant sections.
Please ensure that your application includes all required supporting documents:
Curriculum Vitae (CV)
Supporting Statement
Academic Certificates and Transcripts
Incomplete or late applications will not be considered. Further details are available on our website: BBSRC North West Doctoral Programme in Bioscience | Biology, Medicine and Health | The University of Manchester
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