Genomic and Molecular Medicine

Lead Research Organisation: MRC Clinical Sciences Centre

Abstract

We expect our work to identify new ways of lowering blood cholesterol and triglyceride levels (another type of fat), and thus the risk of heart attacks and angina. Because we are primarily looking for genetic factors that increase the risk of developing high blood cholesterol and triglyceride levels, our work offers the potential of identifying people, at a young age, who have a genetic tendency to develop potentially harmful levels of blood fats and to target these people or advice on diets and/or preventive medicine. High levels of fat in the liver can also lead to potentially fatal liver disease (i.e. cirrhosis). Fatty liver can result from defective transport of fat out of this organ, as well as increased production of fat in the liver. Our second line of research is focussed towards understanding how fat is transported out of enterocytes and hepatocytes into the circulation in special transport carriers. This is expected to suggest new ways of treating post-prandial hyperlipidemia (a major risk factor for atherosclerosis) and fatty liver.

Technical Summary

Genetics and Cell Biology of Human Lipid Disorders that Decrease Survival in Infancy and Adulthood||The overall objective of our programme is to understand the metabolic pathways and intracellular transport systems that co-ordinate whole-body lipid homeostasis. A specific aim is to define the aetiologies of the pernicious lipid profiles of the common, complex genetic disorder, Familial Combined Hyperlipidemia (FCHL) since this group of disorders present a high risk of premature coronary heart disease. Biochemically, the condition is characterised by high blood cholesterol and triglyceride levels, and insulin resistance. In some individuals, high cholesterol level also increases the risk of Alzheimer Disease. In our FCHL studies, we are dissecting the inherited components of the lipid abnormalities. To this end, we are performing genetic studies on large family cohorts and control subjects, and following-up important findings by functional studies. |The aim of the second branch of our programme is to characterise the key proteins of the COP (coat protein) transport machinery that regulate the intracellular transport of chylomicrons (which carry dietary fat into the circulation) and Very Low Density Lipoproteins (transporters of dietary fat and endogenously produced fat) in enterocytes and hepatocytes, respectively. Defects of this system cause Anderson Disease and Chylomicron Retention Disorder, conditions characterised by very severe fat malabsorption and failure to thrive in infancy. Understanding how chylomicrons and Very Low Density Lipoproteins are transported in enterocytes and hepatocytes is important because small molecules that specifically impair this process provide a novel target for ameliorating post-prandial hyperlipidemia, and as such the risk of coronary heart disease. Because the COPII-coated transport system is used by many proteins to reach the Golgi apparatus, our work is important for identifying the different mechanisms used by enterocytes and hepatocytes (and other cell types) to ensure that newly synthesised proteins, as well chylomicrons and very low density lipoproteins, are transported out of the endoplasmic reticulum, to the Golgi apparatus, en route to the circulation.

Publications


10 25 50
Aikio M (2014) Specific collagen XVIII isoforms promote adipose tissue accrual via mechanisms determining adipocyte number and affect fat deposition. in Proceedings of the National Academy of Sciences of the United States of America
Motazacker MM (2013) Evidence of a polygenic origin of extreme high-density lipoprotein cholesterol levels. in Arteriosclerosis, thrombosis, and vascular biology
Shoulders CC (2008) The FTO (fat mass and obesity-associated) gene: big in adipocyte lipolysis? in Journal of lipid research
Shoulders CC (2010) A new Thematic Series: genetics of human lipid diseases. in Journal of lipid research
 
Description Genomics England
Geographic Reach National 
Policy Influence Type Influenced training of practitioners or researchers
Impact Improved knowledge in Genomics
 
Description Heart UK
Geographic Reach Multiple continents/international 
Policy Influence Type Influenced training of practitioners or researchers
 
Description British Heart Foundation Project Grant
Amount £177,679 (GBP)
Organisation British Heart Foundation (BHF) 
Sector Charity/Non Profit
Country United Kingdom of Great Britain & Northern Ireland (UK)
Start 09/2016 
End 09/2020
 
Description British Medical Association Award
Amount £13,000 (GBP)
Organisation British Medical Association (BMA) 
Sector Learned Society
Country United Kingdom of Great Britain & Northern Ireland (UK)
Start 09/2011 
End 09/2012
 
Description Clinical Fellow
Amount £183,753 (GBP)
Organisation The Wellcome Trust Ltd 
Department Wellcome Trust Research Training Fellowship
Sector Charity/Non Profit
Country United Kingdom of Great Britain & Northern Ireland (UK)
Start 09/2013 
End 03/2015
 
Description Joan Adams Fellowship Queen Mary University of London
Amount £100,000 (GBP)
Organisation Queen Mary University of London (QMUL) 
Sector Academic/University
Country United Kingdom of Great Britain & Northern Ireland (UK)
Start 01/2010 
End 12/2011
 
Description Marie Sklodowska-Curie Actions. Innovative Training Network
Amount € 481,774 (EUR)
Organisation European Social Survey: European Research Infrastructure Consortium (ESS ERIC) 
Sector Charity/Non Profit
Country European Union (EU)
Start 03/2017 
End 08/2020
 
Title FCHL cohort 
Description Largest cohort of families with the highly atherogenic condition, Familial Combined Hyperlipidemia 
Type Of Material Biological samples 
Provided To Others? No  
Impact Publications, BMA award and establishment of international collaborations 
URL http://www.jlr.org/content/54/12/3491.long
 
Description Atherosclerosis Trib1 
Organisation University of Sheffield
Country United Kingdom of Great Britain & Northern Ireland (UK) 
Sector Academic/University 
PI Contribution Analysis of gene expression data and lipid measurements. Writing of manuscript and experimental design.
Collaborator Contribution Development of an animal model of atherosclerosis
Impact Multi-disciplinary. Starting point for a PhD project, plus preliminary data for securing further research funding.
Start Year 2017
 
Description PFIDO 
Organisation Cancer Research UK (CRUK)
Department Cancer Research UK London Research Institute (LRI)
Country United Kingdom of Great Britain & Northern Ireland (UK) 
Sector Charity/Non Profit 
PI Contribution PMID: 22399572
Collaborator Contribution Provision of microarray datasets and some data analyses
Impact PMID: 22399572
Start Year 2009
 
Description PFIDO 
Organisation Imperial College London (ICL)
Country United Kingdom of Great Britain & Northern Ireland (UK) 
Sector Academic/University 
PI Contribution PMID: 22399572
Collaborator Contribution Provision of microarray datasets and some data analyses
Impact PMID: 22399572
Start Year 2009
 
Description PFIDO 
Organisation King's College London (KCL)
Country United Kingdom of Great Britain & Northern Ireland (UK) 
Sector Academic/University 
PI Contribution PMID: 22399572
Collaborator Contribution Provision of microarray datasets and some data analyses
Impact PMID: 22399572
Start Year 2009
 
Description PFIDO 
Organisation Sage Bionetworks
Country United States of America 
Sector Charity/Non Profit 
PI Contribution PMID: 22399572
Collaborator Contribution Provision of microarray datasets and some data analyses
Impact PMID: 22399572
Start Year 2009
 
Description TRAIN 
Organisation CIC bioGUNE
Country Spain, Kingdom of 
Sector Private 
PI Contribution Scientific Expertise in genetics, genomics and lipids
Collaborator Contribution Expertise in macrophage biology, prostate cancer, drug discovery, RNAseq, animal models
Impact ITN award from European Union supporting 15 PhD students across Europe, including two at Queen Mary University of London. It is multi-disciplinary-involving multiple P.I.s with unique expertise, as well as two Biotech companies.
Start Year 2015
 
Description TRAIN 
Organisation Helmholtz Association of German Research Centres
Department Helmholtz Zentrum München
Country Germany, Federal Republic of 
Sector Public 
PI Contribution Scientific Expertise in genetics, genomics and lipids
Collaborator Contribution Expertise in macrophage biology, prostate cancer, drug discovery, RNAseq, animal models
Impact ITN award from European Union supporting 15 PhD students across Europe, including two at Queen Mary University of London. It is multi-disciplinary-involving multiple P.I.s with unique expertise, as well as two Biotech companies.
Start Year 2015
 
Description TRAIN 
Organisation Intelligent Pharma
Country Spain, Kingdom of 
Sector Private 
PI Contribution Scientific Expertise in genetics, genomics and lipids
Collaborator Contribution Expertise in macrophage biology, prostate cancer, drug discovery, RNAseq, animal models
Impact ITN award from European Union supporting 15 PhD students across Europe, including two at Queen Mary University of London. It is multi-disciplinary-involving multiple P.I.s with unique expertise, as well as two Biotech companies.
Start Year 2015
 
Description TRAIN 
Organisation San Carlos University Hospital (Hospital Clínico Universitario San Carlos)
Country Spain, Kingdom of 
Sector Hospitals 
PI Contribution Scientific Expertise in genetics, genomics and lipids
Collaborator Contribution Expertise in macrophage biology, prostate cancer, drug discovery, RNAseq, animal models
Impact ITN award from European Union supporting 15 PhD students across Europe, including two at Queen Mary University of London. It is multi-disciplinary-involving multiple P.I.s with unique expertise, as well as two Biotech companies.
Start Year 2015
 
Description TRAIN 
Organisation SeqOmics Biotechnology Ltd
Country Hungary, Republic of 
Sector Private 
PI Contribution Scientific Expertise in genetics, genomics and lipids
Collaborator Contribution Expertise in macrophage biology, prostate cancer, drug discovery, RNAseq, animal models
Impact ITN award from European Union supporting 15 PhD students across Europe, including two at Queen Mary University of London. It is multi-disciplinary-involving multiple P.I.s with unique expertise, as well as two Biotech companies.
Start Year 2015
 
Description TRAIN 
Organisation University Medical Center Utrecht (UMC)
Country Netherlands, Kingdom of the 
Sector Academic/University 
PI Contribution Scientific Expertise in genetics, genomics and lipids
Collaborator Contribution Expertise in macrophage biology, prostate cancer, drug discovery, RNAseq, animal models
Impact ITN award from European Union supporting 15 PhD students across Europe, including two at Queen Mary University of London. It is multi-disciplinary-involving multiple P.I.s with unique expertise, as well as two Biotech companies.
Start Year 2015
 
Description TRAIN 
Organisation University of Beira Interior
Country Portugal, Portuguese Republic 
Sector Academic/University 
PI Contribution Scientific Expertise in genetics, genomics and lipids
Collaborator Contribution Expertise in macrophage biology, prostate cancer, drug discovery, RNAseq, animal models
Impact ITN award from European Union supporting 15 PhD students across Europe, including two at Queen Mary University of London. It is multi-disciplinary-involving multiple P.I.s with unique expertise, as well as two Biotech companies.
Start Year 2015
 
Description TRAIN 
Organisation University of Nantes
Country France, French Republic 
Sector Academic/University 
PI Contribution Scientific Expertise in genetics, genomics and lipids
Collaborator Contribution Expertise in macrophage biology, prostate cancer, drug discovery, RNAseq, animal models
Impact ITN award from European Union supporting 15 PhD students across Europe, including two at Queen Mary University of London. It is multi-disciplinary-involving multiple P.I.s with unique expertise, as well as two Biotech companies.
Start Year 2015
 
Description TRAIN 
Organisation University of Sheffield
Country United Kingdom of Great Britain & Northern Ireland (UK) 
Sector Academic/University 
PI Contribution Scientific Expertise in genetics, genomics and lipids
Collaborator Contribution Expertise in macrophage biology, prostate cancer, drug discovery, RNAseq, animal models
Impact ITN award from European Union supporting 15 PhD students across Europe, including two at Queen Mary University of London. It is multi-disciplinary-involving multiple P.I.s with unique expertise, as well as two Biotech companies.
Start Year 2015
 
Description Thematic Review 
Organisation University of Modena and Reggio Emilia
Department Department of Biomedical Sciences
Country Italy, Italian Republic 
Sector Academic/University 
PI Contribution Wrote the most comprehensive review on the genetic determinants regulating blood cholesterol levels
Collaborator Contribution New biological insights
Impact Publication
Start Year 2010
 
Description Trib1 miRNA 
Organisation University of Sheffield
Country United Kingdom of Great Britain & Northern Ireland (UK) 
Sector Academic/University 
PI Contribution Co-applicant on successful British Heart Foundation grant. Experimental design and data interpretation.
Collaborator Contribution Preliminary data showing that both cytokines and a specific RNA modulate Trib1 activity in vitro and an establishment of an in vivo model to test physiological significance.
Impact Multi-disciplinary. Secured funds from the British Heart Foundation and European Union to complete the analysis of the role of a specific miRNA in regulating Tribbles 1 expression.
Start Year 2016
 
Description Ann Harbor Michigan 
Form Of Engagement Activity Participation in an activity, workshop or similar
Part Of Official Scheme? No
Geographic Reach International
Primary Audience Professional Practitioners
Results and Impact Lecture and Research Discussions. Potential Future Collaborations
Year(s) Of Engagement Activity 2014
 
Description Chair, Heart Reseach UK, cholesterol charity 
Form Of Engagement Activity Participation in an activity, workshop or similar
Part Of Official Scheme? Yes
Geographic Reach International
Primary Audience Patients, carers and/or patient groups
Results and Impact Vigorous questioning of presentations,contributing to decisions regarding awards. Increasing Knowledge base and student training

New ideas
Year(s) Of Engagement Activity 2010,2011,2012,2015
 
Description Leicester 
Form Of Engagement Activity A talk or presentation
Part Of Official Scheme? No
Geographic Reach Local
Primary Audience Professional Practitioners
Results and Impact Informing Geneticists of Processes Perturbed in Human Lipid Diseases
Year(s) Of Engagement Activity 2016
 
Description Oulu 
Form Of Engagement Activity Participation in an activity, workshop or similar
Part Of Official Scheme? No
Geographic Reach International
Primary Audience Postgraduate students
Results and Impact Discussion around the Hype of Personalized Medicine
Year(s) Of Engagement Activity 2015
 
Description University (Sheffield) 
Form Of Engagement Activity A talk or presentation
Part Of Official Scheme? No
Type Of Presentation Keynote/Invited Speaker
Geographic Reach National
Primary Audience Other academic audiences (collaborators, peers etc.)
Results and Impact Sorting out Intracellular Lipid Transport & Secretion in Human Lipid Diseases

Potential future collaboration
Year(s) Of Engagement Activity 2013