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Small molecules to manipulate insulin and IGF-1 signaling.

PGR-P-188

Key facts

Type of research degree
4 year PhD
Application deadline
Ongoing deadline
Country eligibility
International (outside UK)
Funding
Non-funded
Supervisors
Dr Katie Simmons
Additional supervisors
Professor MT Kearney and Dr K J Simmons
Schools
School of Medicine
Research groups/institutes
Leeds Institute of Cardiovascular and Metabolic Medicine
<h2 class="heading hide-accessible">Summary</h2>

Type 2 diabetes mellitus- where the body produces insufficient amounts of insulin or the insulin that is produced does not function properly to control blood glucose-is an increasingly common disorder. Around 2.9 million people in the UK are affected by diabetes and there are estimates of another 850 000 undiagnosed cases. Insulin resistance, which precedes the development of type 2 diabetes by many years, is also an independent risk factor for the development of premature cardiovascular disease. It is well established that IGF-1R and IR are able to form hybrid receptors consisting of an IR ?? heterodimer and an IGF1R ?? heterodimer. IR: IGF1R stoichiometry is a critical determinant in endothelial cell insulin sensitivity, nitric oxide bioavailability and vascular repair, the mechanism of which being a negative effect of the IGF-1R on insulin signaling by forming insulin resistant hybrid receptors with IR. (1)

<h2 class="heading hide-accessible">Full description</h2>

<p>Using a homology model of the IR:IGF-1R hybrid structure(2, 3) and hotspot prediction software to predict the key regions involved in hybrid dimer formation together with virtual high-throughput screening tools(4, 5), you will identify small molecules which are predicted to inhibit formation of the IR:IGF-1R hybrids. You will screen these using a Bioluminescence Resonance Energy Transfer assay(6) to measure the interaction of the IR and IGF-1R monomers and thereby quantify the action of small molecule probes on selectively inhibiting dimer formation.</p> <p>Structural studies to characterize the IR:IGF1R dimer structure and its perturbation by small molecules, will also be carried out using Electron Microscopy(7).</p> <p><strong>References:</strong></p> <p>Gatenby, V.K. Imrie, H. and Kearney, M. The IGF-1 receptor and regulation of nitric oxide bioavailability and insulin signalling in the endothelium. Pflugers Archiv : European journal of physiology. 2013, 465(8), pp.1065-74.</p> <p>Croll, T.I. Smith, B.J. Margetts, M.B. Whittaker, J. Weiss, M.A. Ward, C.W. and Lawrence, M.C. Higher-Resolution Structure of the Human Insulin Receptor Ectodomain: Multi-Modal Inclusion of the Insert Domain. Structure. 2016, 24(3), pp.469-76.</p> <p>Yang, J. Yan, R. Roy, A. Xu, D. Poisson, J. and Zhang, Y. The I-TASSER Suite: protein structure and function prediction. Nature methods. 2015, 12(1), pp.7-8.</p> <p>Sterling, T. and Irwin, J.J. ZINC 15-Ligand Discovery for Everyone. J Chem Inf Model. 2015, 55(11), pp.2324-2337.</p> <p>Halgren, T.A. Murphy, R.B. Friesner, R.A. Beard, H.S. Frye, L.L. Pollard, W.T. and Banks, J.L. Glide: A new approach for rapid, accurate docking and scoring. 2. Enrichment factors in database screening. J Med Chem. 2004, 47(7), pp.1750-1759.</p> <p>Blanquart, C. Gonzalez-Yanes, C. and Issad, T. Monitoring the activation state of insulin/insulin-like growth factor-1 hybrid receptors using bioluminescence resonance energy transfer. Molecular pharmacology. 2006, 70(5), pp.1802-11.</p> <p>Smith, M.T. and Rubinstein, J.L. Structural biology. Beyond blob-ology. Science. 2014, 345(6197), pp.617-9.</p>

<h2 class="heading">How to apply</h2>

<p>Please note these are not standalone projects and applicants must apply to the PhD academy 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:fmhpgradmissions@leeds.ac.uk">fmhpgradmissions@leeds.ac.uk</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:fmhpgradmissions@leeds.ac.uk">fmhpgradmissions@leeds.ac.uk</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&#39;s minimum English language requirements (below).</p>

<h2 class="heading heading--sm">Entry requirements</h2>

A degree in biological sciences, dentistry, medicine, midwifery, nursing, psychology or a good honours degree in a subject relevant to the research topic. A Masters degree in a relevant subject may also be required in some areas of the Faculty. For entry requirements for all other research degrees we offer, please contact us.

<h2 class="heading heading--sm">English language requirements</h2>

Applicants whose first language is not English must provide evidence that their English language is sufficient to meet the specific demands of their study. The Faculty of Medicine and Health minimum requirements in IELTS and TOEFL tests for PhD, MSc, MPhil, MD are: &acirc;&euro;&cent; British Council IELTS - score of 7.0 overall, with no element less than 6.5 &acirc;&euro;&cent; TOEFL iBT - overall score of 100 with the listening and reading element no less than 22, writing element no less than 23 and the speaking element no less than 24.

<h2 class="heading">Contact details</h2>

<p>For further information please contact the Graduate School Office<br /> e:<a href="mailto:fmhpgradmissions@leeds.ac.uk">fmhpgradmissions@leeds.ac.uk</a> t: +44 (0)113 343 8221.</p>


<h3 class="heading heading--sm">Linked research areas</h3>