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(MRC CASE) The haemoglobin adductome as a biomarker of disease onset and progression in obese patients.

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  • Full or part time
    Dr A Povey
    Prof G Margison
    Dr H Soran
  • Application Deadline
    No more applications being accepted
  • Competition Funded PhD Project (European/UK Students Only)
    Competition Funded PhD Project (European/UK Students Only)

Project Description

Obesity increases the risk of many diseases including cancer and diabetes and though many obesity risk factors have been identified, environmental factors are increasingly recognised as determinants of disease onset and progression and are potentially modifiable by lifestyle choices or changes in diet1. Our hypothesis is that such exposures may be detected by their covalent interactions with proteins to form a protein adductome that can be a marker of both a healthy lifestyle and also disease outcome. The challenge is to establish and apply ultrasensitive and precise methodologies to characterise this human protein adductome. Previous studies have focussed on modifications to selected individual amino acids in blood proteins, including cysteine 34 of serum albumin2 and the amino-terminal valine in hemoglobin (alpha chain; HbA1)3 and indeed glycated Hb measurement has been described4. This restricts the potential breadth of the analyses in that such exposures may potentially result in modifications at numerous sites within proteins which can be a better exposure fingerprint and may provide more selective and sensitive markers of disease outcome. In the present proposal, the exquisite precision and sensitivity of state of the art Liquid Chromatography (LC) coupled to Mass Spectrometry (MS) will be exploited to initially define all detectable covalent modifications to amino acids in HbA1. To facilitate this, recombinant and purified human HbA1 will be reacted in vitro with a wide range of chemicals including reactive oxygen and nitrogen species, digested with proteases and analysed using various MS platforms in order to define HbA1-adduct molecular fingerprints. Concurrently a longitudinal study of obese patients undergoing bariatric surgery will be undertaken in which detailed demographic, lifestyle and dietary information will be collected along with blood samples pre- and post-treatment. Blood samples will be processed and purified HbA1 will be analysed using developed methodologies. The human adductome will be characterised in terms of (i) the spectrum of adducts present and their amounts and (ii) those adducts whose levels have been modified by treatment. Furthermore, the associations will be assessed between adducts and lifestyle, diet and other variables and, on follow-up, with clinical outcomes. The increasing incidence of obesity and its consequential diseases make this a suitable subject for precision medicine-based health improvements and the developed approaches off the means and opportunity to do this not only in these patients but in a wider range of different patient populations where disease progression is potentially modifiable by lifestyle choices and diet.

References
1Huang M. et al. (2018) Sci Total Env. 631-632; 589-596 ; 2 Grigoryan H. et al. (2016) Anal. Chem. , 88, 10504−10512; 3 Carlsson H. et al. (2019) High-Throughput. 8, 6, 1-18; 4 Hattan S.J. et al (2016) J Am Soc Mass Spectrom. 27, 532-541

Entry Requirements
Applications are invited from UK/EU nationals only. Applicants must have obtained, or be about to obtain, at least an upper second class honours degree (or equivalent) in a relevant subject.

Funding Notes

This is a CASE studentship in partnership with Waters and will be funded under the MRC Doctoral Training Programme. If you are interested in this project, please make direct contact with the Supervisor to discuss the project further as soon as possible. You MUST also submit an online application form - full details on how to apply can be found here https://www.bmh.manchester.ac.uk/study/research/mrc-dtp/apply/.

As an equal opportunities institution we welcome applicants from all sections of the community regardless of gender, ethnicity, disability, sexual orientation and transgender status. All appointments are made on merit.

References

Hale OJ, Ryumin P, Brown JM, Morris M, Cramer R. (2018) Production and analysis of multiply charged negative ions by liquid atmospheric pressure matrix-assisted laser desorption/ionization mass spectrometry. Rapid Commun Mass Spectrom. Aug 1. doi: 10.1002/rcm.8246.

Potjewyd G, Day PJ, Shangula S, Margison GP, Povey AC. (2017) L-β-N-methylamino-l-alanine (BMAA) nitrosation generates a cytotoxic DNA damaging alkylating agent: An unexplored mechanism for neurodegenerative disease. Neurotoxicology 59: 105-109.

Steckling N, Gotti A, Bose-O'Reilly S, Chapizanis D, Costopoulou D, De Vocht F, Garí M, Grimalt JO, Heath E, Hiscock R, Jagodic M, Karakitsios SP, Kedikoglou K, Kosjek T, Leondiadis L, Maggos T, Mazej D, Polańska K, Povey A, Rovira J, Schoierer J, Schuhmacher M, Špirić Z, Stajnko A, Stierum R, Tratnik JS, Vassiliadou I, Annesi-Maesano I, Horvat M, Sarigiannis DA. (2018) Biomarkers of exposure in environment-wide association studies - Opportunities to decode the exposome using human biomonitoring data. Environ Res. 164:597-624.

Theisen A, Yan B, Brown JM, Morris M, Bellina B, Barran PE. (2016) Use of Ultraviolet Photodissociation Coupled with Ion Mobility Mass Spectrometry To Determine Structure and Sequence from Drift Time Selected Peptides and Proteins. Anal Chem. 88: 9964-9971

Yadav R, Hama S, Liu Y, Siahmansur T, Schofield J, Syed AA, France M, Pemberton P, Adam S, Ho JH, Aghamohammadzadeh R, Dhage S, Donn R, Malik RA, New JP, Jeziorska M, Durrington P, Ammori BA, Soran H. (2017) Effect of Roux-en-Y Bariatric Surgery on Lipoproteins, Insulin Resistance, and Systemic and Vascular Inflammation in Obesity and Diabetes. Front Immunol. 8: 1512.



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