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Cryo electron microscopy to study innate immune complexes on the surface of cancer cells

  • Full or part time
  • Application Deadline
    Friday, May 31, 2019
  • Self-Funded PhD Students Only
    Self-Funded PhD Students Only

Project Description

Blood vessels of tumors carry specific markers on the cell surface. The innate immune system consisting of complement proteins and white blood cells (macrophages) are involved in the recognition and destruction of cancer cells. Overexpression of complement receptor gC1qR has been reported in many forms of cancer and correlated with poor prognosis. Tumour homing peptides have been shown to recognise gC1qR and supress tumour growth. As well as being a receptor for complement gC1qR is the major zinc dependent high affinity receptor for assembly and activation of proteins from the contact system. Contact factors Factor XII, prekallikrein, are serine proteases and together with the co-factor kininogen utilise key protein modules to mediate binding interactions to gC1qR and diverse ligands which regulate protease activation and function in innate immunity. The contact system is central to crosstalk between coagulation and inflammation and constitutes the unifying principle for diverse disorders including cancer, hereditary angiodema and cerebrovascular diseases such as alzheimers, stroke. Contact activation can trigger both plasma coagulation via the intrinsic pathway (via Factor XI) and contribute to inflammation via bradykinin release. To advance this important area we will study the molecular basis of how contact factors assemble on the cancer cells using Cryo-electron microscopy. The long term goal is to determine the high resolution structure of macromolecule complexes and determine the organising principle determining how contact proteins and gC1qR organise on the cell surface and this will provide a scaffold to develop antagonists and therapies for diverse diseases.

References

Front Med (Lausanne). 2018 Mar 21;5:66. Cell Receptor and Cofactor Interactions of the Contact Activation System and Factor XI. Pathak 1, Kaira BG, Slater A, Emsley J.

How good is research at University of Nottingham in Allied Health Professions, Dentistry, Nursing and Pharmacy?
Pharmacy

FTE Category A staff submitted: 44.10

Research output data provided by the Research Excellence Framework (REF)

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