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

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.