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Targeting ABCB4 insufficiency to treat obstetric cholestasis in the East London Asian population


Blizard Institute

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Prof K Linton , Dr S Iliodromiti No more applications being accepted Competition Funded PhD Project (European/UK Students Only)

About the Project

Why is obstetric cholestasis more prevalent in the East London Asian community and what can we do about it?
Obstetric cholestasis (OC), the impairment of bile flow from the liver during pregnancy, is a serious condition which causes substantial perinatal mortality and morbidity, including preterm labour, foetal asphyxia and stillbirth (1). Women typically present with gestational pruritis and are found to have raised serum bile acids which worsen over the course of pregnancy. There is a much higher risk of developing pre-eclampsia and gestational diabetes, and there are no effective treatments (2). It has long been recognised that this condition disproportionately affects Asian populations but the reasons for this are unclear. Caucasian OC has a strong genetic component, primarily involving the genes responsible for bile formation, bile flow from the liver and the integrity of the canalicular membrane lining the biliary tree. These studies have identified multiple mutations in the ABCB4 gene. ABCB4 encodes the transporter protein that effluxes the lipid component of the bile into the bile canaliculi. Failure to transport the lipid results in toxic bile with high detergent activity which damages the hepatocytes from the lumen of the biliary tree. We expect to find novel mutations in ABCB4 in the East London population as well mutations in the other bile transporters such as the bile salt export pump (BSEP).
We propose a multidisciplinary approach to investigate, characterise and intervene in OC within the East London community. The three main strands of this bedside to bench and back again project are:
1. Genetic Analyses: Interrogation of the East London Genes and Health database that links the genome sequences and health records of 100,000 Bangladeshi and Pakistani patients (http://www.genesandhealth.org/). This will determine the variants in the candidate OC genes of the local population. The approach will be complemented by recruitment of new patients presenting with OC to Barts Health Trust.
2. Cell Biology: Characterization of the impact on protein function in vitro to determine whether the variants identified are causative for OC (3,6).
3. Pharmacology: Identification of small molecules which improve the stability and function of bile flow transporters by screening a drug library (unpublished data developed from reference 4).
The multidisciplinary approach is matched by the supervisory team of Prof Linton, an academic with a research focus on the bile flow transporters at the molecular level (3,4,5,6), Dr Iliodromiti, a clinical academic Obstetrician whose research is in perinatal epidemiology (7,8,9), and Prof Alazawi, a clinical academic Hepatologist with a focus on inflammatory signalling and metabolism within the liver (10,11,12,13).
The project would suit a trainee general physician or specialist in hepatology, women’s health, obstetrics or population genetics. Training will be provided in all techniques by the supervisory team and the student will benefit from close, collaborative links with our colleagues at King’s College with a shared interest in OC (see references below). The project provides ample scope for creativity and development of critical thinking in a clinical academic setting and an excellent prospect of high impact publications.

How to apply
To apply, please click the 'institution website' button.

The successful candidate must be a registered clinician in the UK.

Funding Notes

These studentships will fund a student with a clinical qualification and GMC / GDC registration at any career stage below consultant. They will be funded for three years at current MRC rates. Studentships will include PhD fees (at home/EU levels) and up to £6000 pa for consumables. Further consumables / funding for travel may be available on application.

References

1. Ovadia et al., Association of adverse perinatal outcomes of intrahepatic cholestasis of pregnancy with biochemical markers: results of aggregate and individual patient data meta-analyses. Lancet (2019) 383: 899-909.
2. Chappell et al., Ursodeoxycholic acid versus placebo in women with intrahepatic cholestasis of pregnancy (PITCHES): a randomised controlled trial. Lancet (2019) 394:849-60
3. Andress et al. ABCB4 missense mutations D243A, K435T, G535D, I490T, R545C, and S978P significantly impair the lipid floppase and likely predispose to secondary pathologies in the human population. Cell Mol Life Sci (2017) 74: 2513-24.
4. Andress et al. Molecular mechanistic explanation for the spectrum of cholestatic disease caused by the S320F variant of ABCB4. Hepatology (2014), 59: 1921-31.
5. Groen et al. The flippase ATP8B1 counteracts the deleterious function of floppase ABCB4 to maintain hepatocanalicular membrane integrity. Gastroenterol. (2011) 141, 1927-37.
6. Byrne et al. The human bile salt export pump: characterization of substrate specificity and identification of inhibitors. Gastroenterology (2002) 123, 1649-58.
7. Iliodromiti et al. Customised and noncustomised birth weight centiles and prediction of stillbirth and infant mortality and morbidity: A Cohort Study of 979,912 Term Singleton Pregnancies in Scotland. PLoS Med. (2017) Jan 31;14(1):e1002228.
8. Iliodromiti et al. Accuracy of circulating adiponectin for predicting gestational diabetes: a systematic review and meta-analysis. Diabetologia. (2016) Jan 14.
9. Iliodromiti et al. Apgar score and neonatal, infant and cause specific mortality: a population based cohort study of 1,029,207 infants. Lancet. (2014) Nov 15;384(9956):1749- 55.
10. Heath et al. Stat2 loss disrupts damage signalling and is protective in acute pancreatitis. J Path (2020) 252:41-52
11. Waller et al., ADAM17-mediated reduction in CD14++CD16+ monocytes ex vivo and reduction in intermediate monocytes with immune paresis in acute pancreatitis and acute alcoholic hepatitis. Frontiers in Immunology. (2019) Aug 10: 1902.
12. Alexander et al., Risks and clinical predictors of cirrhosis and hepatocellular carcinoma diagnoses in adults with diagnosed NAFLD: real-world study of 18 million patients in four European cohorts. BMC Medicine. (2019) May 20;17(1):95.
13. De Silva et al., Non-invasive markers of liver fibrosis in fatty liver disease are unreliable in people of South Asian descent. Front Gastro (2017) 9(2):115-121.
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