ProfessorCatherine Williamson

1. The molecular aetiology of intrahepatic cholestasis of pregnancy (ICP) and related fetal complications.

· Genomic studies of a resource comprising >1000 DNA samples from women with ICP and >1000 control samples.
· Whole-genome sequencing of >300 samples from women with severe, early-onset ICP.
· Functional studies of genetic variation identified in the genes that encode the principal bile acid receptor, FXR, and biliary transporters (ABCB4, ABCB11).
· Identification of new candidate genes and evaluation of genetic susceptibility in women of different ethnic origins.
· In vivo studies of the influence of pregnancy and reproductive hormones on bile acid and glucose homeostasis in mice deficient in FXR and the related nuclear receptor TGR5.
· In vitro studies of the influence of estrogen, progesterone, and their metabolites on bile acid homeostasis in hepatocytes.
· Aetiology of stillbirth in ICP.
· Evaluation of bile acids as biomarkers to enable the prediction of high-risk pregnancies.
· Mechanisms of fetal arrhythmia (and potentially stillbirth), including bile acid impact on cardiac rhythm and calcium dynamics in cardiomyocytes.
· Mechanisms of spontaneous preterm birth in ICP.
· Investigation of mechanisms of action of ursodeoxycholic acid (UDCA), nor-UDCA, rifampicin, metformin, and novel drugs with potential to treat ICP, e.g., IBAT inhibitors.
· Randomized, controlled trial of IBAT inhibitor vs placebo and collection of samples for mechanistic studies.
· Subsequent health of mothers and infants of pregnancies complicated by ICP.
· Development of a bedside sensor for bile acids.

2. The molecular aetiology of metabolic disorders of pregnancy

· Investigation of the influence of gestational hormones on metabolic alterations with advancing pregnancy, including studies of liver, adipose tissue (WAT and BAT), muscle, islets, and enterocytes.
· Mechanisms underlying susceptibility to gestational diabetes mellitus (GDM).
· Study of enteroendocrine signals, gut metabolome, microbiome, and metagenomics in normal pregnancy, ICP, and GDM.
· In vivo studies of drugs that modulate bile acid signaling as potential treatments for GDM.
· Clinical lead for 2 clinical trials to evaluate the efficacy of UDCA as a treatment for GDM
i. GUARD trial (UK): evaluation of the impact of metformin on gut signaling
ii. GUARDS trial (Spain): evaluation of the impact of UDCA vs placebo on maternal glycemic control in women with GDM
· Clinical and genomic studies of hyperemesis gravidarum (via NIHR BioResource Rare Disease consortium, UK)
· Evaluation of the impact of nutrient deficiency in hyperemesis gravidarum on maternal and child health

3. Early-life interventions to prevent childhood obesity and associated cardio-metabolic risk factors

· Novel interventions for children and young people to be used alongside current conventional dietary and exercise therapies. These interventions include intermittent cold exposure (ICE), bile acid therapies, and modulation of the gut microbiota to activate brown adipose tissue and cause browning of white adipose tissue
· Evaluation of markers associated with maternal metabolic diseases that result in offspring susceptibility to obesity and associated cardio-metabolic risk factors.
· Investigation of the impact of paternal cholestasis on offspring susceptibility to cardio-metabolic abnormalities and the utility of paternal treatments, e.g., the drug ursodeoxycholic acid, to improve offspring health.

4. Genomic evaluation of susceptibility to preterm birth

· The PRESTIGE-PTB study is a national, multicenter cohort study that will investigate the genetic factors that influence susceptibility to spontaneous preterm birth. This is a collaboration between Tommy’s and Genomics England led by Catherine Williamson and Peter Dixon at Imperial
· Evaluation of genomic susceptibility to preterm birth in women of different ethnic backgroundsent ethnic backgrounds