The induction of immune responses to tumours can provide long-lasting protection from cancer. In this regard, T cells can suppress tumour growth by directly killing cancer cells and by producing inflammatory cytokines. Furthermore, advances in immunotherapy have shown the adoptive cell transfer (ACT) of tumour-reactive T cells to be a successful approach to the treatment of cancer. However, in many individuals the T cell response to cancer is ineffective. It has become apparent that the processes of T cell activation and differentiation are linked to the regulation of basic metabolic pathways. These pathways provide energy required for growth, proliferation and effector functions. Dysregulation of cellular metabolism has been linked to the failure of anti-tumour T cell responses. Therefore, a greater understanding of the key pathways and regulators of T cell metabolism has the potential to define new therapeutic targets and approaches to manipulate T cell responses in the clinic. The primary supervisor’s research team has determined that a mitochondrial metabolic enzyme, PEPCK2, plays an important role in the differentiation and effector function of inflammatory CD8+ and CD4+ T cells.
<p>Objectives:</p> <p>This project will build upon initial findings to:</p> <p>1. Determine the impact of pharmacological and genetic inhibition of PEPCK2, and the related PEPCK1, on mouse T cell activation, differentiation and effector function</p> <p>2. Investigate the role of PEPCKs in T cell metabolism</p> <p>3. Determine how manipulation of PEPCK2 expression might be harnessed to improve the efficacy of anti-tumour T cell responses using <em>in vivo </em>mouse models</p> <p><strong>References:</strong></p> <p>1. The tyrosine phosphatase PTPN22 discriminates weak self peptides from strong agonist TCR signals. Salmond RJ, Brownlie RJ, Morrison VL, Zamoyska R. Nat. Immunol. 2014, 15:875-883</p> <p>2. Resistance to TGFb suppression and improved anti-tumor responses in CD8+ T cells lacking PTPN22. Brownlie RJ, Garcia C, Ravasz M, Zehn D, Salmond RJ, Zamoyska R. Nat. Commun. 2017, 7:1343</p> <p>3. mTOR regulation of glycolytic metabolism in T cells. Salmond RJ. Front Cell Dev Biol. 2018, 6:122.</p>
<p>Please note these are not standalone projects and applicants must apply to the <a href="https://medicinehealth.leeds.ac.uk/leeds-institute-research-st-james/doc/international-phd-academy-medical-research">PhD academy</a> directly.</p> <p>Applications can be made at any time. To apply for this project applicants should complete a<a href="https://medicinehealth.leeds.ac.uk/downloads/download/129/faculty_graduate_school_-_application_form"> Faculty Application Form</a> and send this alongside a full academic CV, degree transcripts (or marks so far if still studying) and degree certificates to the Faculty Graduate School <a href="mailto:email@example.com">firstname.lastname@example.org</a></p> <p>We also require 2 academic references to support your application. Please ask your referees to send these <a href="https://medicinehealth.leeds.ac.uk/downloads/download/130/faculty_graduate_school_-_scholarship_reference_form">references</a> on your behalf, directly to <a href="mailto:email@example.com">firstname.lastname@example.org</a></p> <p>If you have already applied for other projects using the Faculty Application Form this academic session you do not need to complete this form again. Instead you should email fmhgrad to inform us you would like to be considered for this project.</p> <p>If English is not your first language, you must provide evidence that you meet the University's minimum English language requirements (below).</p> <p><em>We welcome applications from all suitably-qualified candidates, but UK black and minority ethnic (BME) researchers are currently under-represented in our Postgraduate Research community, and we would therefore particularly encourage applications from UK BME candidates. All scholarships will be awarded on the basis of merit.</em></p>
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