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Translational Cardiovascular Research, Cross-talk between adipose tissue and the cardiovascular system in humans

  • Full or part time
  • Application Deadline
    Friday, January 11, 2019
  • Competition Funded PhD Project (Students Worldwide)
    Competition Funded PhD Project (Students Worldwide)

Project Description

We undertake translational research by moving from bench to bedside and vice versa; our main focus is the cross-talk between adipose tissue and the cardiovascular system.

Using translational approaches, we have been developing novel diagnostic tools using a wide range of techniques such as imaging, novel blood biomarkers etc, for the early detection of cardiovascular diseases and risk stratification. We also work towards the discovery of new therapeutic targets for the prevention and treatment of cardiovascular diseases in the context of obesity and diabetes, as we study the mechanisms by which different adipose tissue depots in the human body affect vascular and myocardial disease pathogenesis with specific focus on changes in redox-sensitive inflammatory mechanisms. Recent work from the group led to the discovery of a novel imaging biomarker, Fat Attenuation Index (Antonopoulos et al Science Transl Med 2017) validated recently in a large prospective study (the CRISP-CT study, Oikonomou et al Lancet 2018).

Our available project will investigate the molecular effects of new therapeutics such as Glucagon-Like Peptide 1 (GLP-1) on cardiovascular biology, by performing ex vivo experiments in human arteries and myocardial tissue, as well as primary cardiovascular cells and adipocytes.

We have established one of the world’s most extensively phenotyped cohorts of patients undergoing cardiac surgery, The Oxford Heart Vessels & Fat (ox-HVF) cohort. This cohort includes more than 1500 patients and consists of a cluster of clinical studies which provide synergistic results allowing the deployment of a multi-level strategy to understand the mechanisms of cardiovascular diseases. The strength of the cohort is the direct access to human tissue that is combined with extensive non-invasive cardiovascular phenotyping, such as cardiovascular computed tomography angiography, ultrasound. During the surgery, samples of arteries, veins, right atrium appendage and adipose tissue from 5 different depots are harvested and partly used in bioassays aiming to characterise in a patient-specific way the paracrine/endocrine interactions between adipose tissue, the vascular wall and the heart. To study how adipocytes communicate with vascular cells in a paracrine way, we isolate pre-adipocytes from perivascular adipose tissue and vascular cells from the underlying human vessels, which are used in co-culture bioassays, enabling better understanding of the cell-cell communication signals between tissues in obesity/insulin resistance, diabetes and other conditions. This approach led us to demonstrate that adipose tissue can secrete a large number of active molecules able to affect cardiovascular redox state in a paracrine and endocrine manner. We have also discovered novel “inside to outside” signals from the cardiovascular system to the adipose tissue that drive the biology of epicardial/perivascular adipocytes, which “sense” cardiovascular inflammation and oxidation modifying their adipogenic capacity and secretory profile; these bi-directional communication channels play a role in the cardiovascular complications of obesity/insulin resistance and diabetes.
The available project will build on this unique and powerful platform (i.e. the Ox-HVF ) and will focus on studying how GLP-1 analogues affect the interplay between adipose tissue and the cardiovascular system, with particular focus on the interactions between GLP-1 signalling and cardiovascular redox regulation. Moreover, a clinical trial has suggested that GLP-1 analogues reduce cardiovascular risk in diabetic patients; however, its role in the cross-talk between adipose tissue and the cardiovascular system has not been established yet. Hence, this project aims to explore this important gap in our knowledge, providing mechanistic insights on GLP-1 signalling as a therapeutic target to prevent cardiovascular disease progression in obesity.

The successful candidate will receive training in several techniques relevant to the execution of the project that are already available in the lab, such as isolation and culturing of primary cells from human vessels, myocardial and fat biopsies; co-culture bioassays; vasomotor studies on human vessels; superoxide measurements on human tissues/cells; pertinent techniques of biochemistry and cellular and molecular biology. The student will be also encouraged to undertake any training outside the lab that is necessary for a successful execution of the project.

As well as the specific training detailed above, students will have access to high-quality training in scientific and generic skills, as well as access to a wide-range of seminars and training opportunities through the many research institutes and centres based in Oxford.

The Department has a successful mentoring scheme, open to graduate students, which provides an additional possible channel for personal and professional development outside the regular supervisory framework. We hold an Athena SWAN Silver Award in recognition of our efforts to build a happy and rewarding environment where all staff and students are supported to achieve their full potential.

Funding Notes

Funding for this project is available to basic scientists through the RDM Scholars Programme, which offers funding to outstanding candidates from any country. Successful candidates will have all tuition and college fees paid and will receive a stipend of £18,000 per annum.

Applications must be received, including all relevant supporting materials, by Friday 11th January 2019 at 12 noon (midday).

Please visit our website for more information on how to apply.

References

Oikonomou EK, Marwan M, Desai MY, Mancio J, Alashi A, Hutt Centeno E, Thomas S, Herdman L, Kotanidis CP, Thomas KE, Griffin BP, Flamm SD, Antonopoulos AS, Shirodaria C, Sabharwal N, Deanfield J, Neubauer S, Hopewell JC, Channon KM, Achenbach S, Antoniades C. Non-invasive detection of coronary inflammation using computed tomography and prediction of residual cardiovascular risk (the CRISP CT study): a post-hoc analysis of prospective outcome data. Lancet. 2018 Sep 15;392(10151):929-939

Oikonomou EK, Antoniades C. Immunometabolic Regulation of Vascular Redox State: The Role of Adipose Tissue. Antioxid Redox Signal. 2018 Jul 20;29(3):313-336

Antonopoulos AS, Sanna F, Sabharwal N, Thomas S, Oikonomou EK, Herdman L, Margaritis M, Shirodaria C, Kampoli AM, Akoumianakis I, Petrou M, Sayeed R, Krasopoulos G, Psarros C, Ciccone P, Brophy CM, Digby J, Kelion A, Uberoi R, Anthony S, Alexopoulos N, Tousoulis D, Achenbach S, Neubauer S, Channon KM, Antoniades C. Detecting human coronary inflammation by imaging perivascular fat. Sci Transl Med. 2017 Jul 12;9(398). pii: eaal2658

Antonopoulos AS, Margaritis M, Verheule S, Recalde A, Sanna F, Herdman L, Psarros C, Nasrallah H, Coutinho P, Akoumianakis I, Brewer AC, Sayeed R, Krasopoulos G, Petrou M, Tarun A, Tousoulis D, Shah AM, Casadei B, Channon KM, Antoniades C. Mutual Regulation of Epicardial Adipose Tissue and Myocardial Redox State by PPAR-γ/Adiponectin Signalling. Circ Res. 2016 Mar 4;118(5):842-55

Antonopoulos AS, Margaritis M, Coutinho P, Shirodaria C, Psarros C, Herdman L, Sanna F, De Silva R, Petrou M, Sayeed R, Krasopoulos G, Lee R, Digby J, Reilly S, Bakogiannis C, Tousoulis D, Kessler B, Casadei B, Channon KM, Antoniades C. Adiponectin as a link between type 2 diabetes and vascular NADPH oxidase activity in the human arterial wall: the regulatory role of perivascular adipose tissue. Diabetes. 2015 Jun;64(6):2207-19

Margaritis M, Antonopoulos AS, Digby J, Lee R, Reilly S, Coutinho P, Shirodaria C, Sayeed R, Petrou M, De Silva R, Jalilzadeh S, Demosthenous M, Bakogiannis C, Tousoulis D, Stefanadis C, Choudhury RP, Casadei B, Channon KM, Antoniades C. Interactions between vascular wall and perivascular adipose tissue reveal novel roles for adiponectin in the regulation of endothelial nitric oxide synthase function in human vessels. Circulation. 2013 Jun 4;127(22):2209-21

How good is research at University of Oxford in Clinical Medicine?

FTE Category A staff submitted: 238.51

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

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