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Click here to search FindAPhD.com for PhD studentship opportunitiesUnderstanding interactions between immune cells and necrotic cells using super-resolution microscopy
Prof D Davis
Applications accepted all year round
About the Project
Background: Whilst chronic tissue damage and cell death is a key consequence of disease, (e.g. Cancer, Lupus, COPD, Stroke, atherosclerosis) many of the fundamental processes of how the cells of the immune system respond to these necrotic cells remains to be elucidated. Recently, significant advances have been made in understanding how cross-presenting dendritic cells use necrotic signals to activate naïve cytotoxic T cells (Ahrens et al., 2012, Sancho et al., 2013, Sancho et al., 2009). By increasing our fundamental knowledge of necrosis one might be able to identify new pathways of intervention to either suppress necrotic cell induced inflammation. Here it might be acting as an adjuvant to the inflammation. Alternatively, it may increase the antigenicity of tumours as potential cancer vaccines.
MedImmune has an established interest in the role Danger Associated Molecular Patterns (DAMPS) and of necrosis in diseases in autoimmunity and respiratory disease. Coupling our interests and collaborations in this field with Prof Davis’s research program to address complex immunology using high resolution imaging of the immune response will allow a more detailed understanding of this mechanism in live cells.
Hypothesis: We hypothesise that necrotic cells activate the immune system in two ways – by directly triggering T and NK cell effector responses such as cytokine secretion and indirectly by facilitating cross-presentation by interactions with APCs. However, it remains unclear how necrosis triggers these processes.
Objectives: We will image the interactions between different types of immune cells and necrotic target cells to determine which proteins accumulate at the synapse, how long contacts endure, and what are the downstream consequences of interactions with necrotic cells
Proposed Outcomes: We aim to establish key factors that allow necrotic cells to prime immune responses – which in turn may seed new ideas for drug targets
MedImmune has an established interest in the role Danger Associated Molecular Patterns (DAMPS) and of necrosis in diseases in autoimmunity and respiratory disease. Coupling our interests and collaborations in this field with Prof Davis’s research program to address complex immunology using high resolution imaging of the immune response will allow a more detailed understanding of this mechanism in live cells.
Hypothesis: We hypothesise that necrotic cells activate the immune system in two ways – by directly triggering T and NK cell effector responses such as cytokine secretion and indirectly by facilitating cross-presentation by interactions with APCs. However, it remains unclear how necrosis triggers these processes.
Objectives: We will image the interactions between different types of immune cells and necrotic target cells to determine which proteins accumulate at the synapse, how long contacts endure, and what are the downstream consequences of interactions with necrotic cells
Proposed Outcomes: We aim to establish key factors that allow necrotic cells to prime immune responses – which in turn may seed new ideas for drug targets
Funding Notes
This 3 year project provides funding for UK/EU students, and covers tuition fees and an enhanced stipend. Applicants from outside of the EU are eligible to apply, but must be able to provide evidence that they can fund the difference in Home and Overseas tuition fees (approximately £12,600 per year)
Applications should be submitted online via http://www.ls.manchester.ac.uk/phdprogrammes
Applications should be submitted online via http://www.ls.manchester.ac.uk/phdprogrammes
References
F-actin is an evolutionarily conserved damage-associated molecular pattern recognized by DNGR-1, a receptor for dead cells. Ahrens S, Zelenay S, Sancho D, Hanč P, Kjær S, Feest C, Fletcher G, Durkin C, Postigo A, Skehel M, Batista F, Thompson B, Way M, Reis e Sousa C, Schulz O. Immunity. 2012 Apr 20;36(4):635-45.
Sensing of cell death by myeloid C-type lectin receptors. Sancho D, Reis E Sousa C. Curr Opin Immunol. 2013 Jan 16
Identification of a dendritic cell receptor that couples sensing of necrosis to immunity. Sancho D, Joffre OP, Keller AM, Rogers NC, Martínez D, Hernanz-Falcón P, Rosewell I, Reis e Sousa C. Nature. 2009 Apr 16;458(7240):899-903.
Sensing of cell death by myeloid C-type lectin receptors. Sancho D, Reis E Sousa C. Curr Opin Immunol. 2013 Jan 16
Identification of a dendritic cell receptor that couples sensing of necrosis to immunity. Sancho D, Joffre OP, Keller AM, Rogers NC, Martínez D, Hernanz-Falcón P, Rosewell I, Reis e Sousa C. Nature. 2009 Apr 16;458(7240):899-903.
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