Research in detail
The group has two main areas of interest:
- The first is the application of state-of-art genetic and genomic approaches such as CRISPR/Cas9 and siRNA silencing, gene over-expression and global gene expression profiling to investigate the major genetic asthma locus (chromosome 17q13) containing the genes ORMDL3 and GSDMB. Work on ORMDL3 and GSDMB (which are co-regulated in the same linkage disequilibrium region) is being conducted using in vitro and in vivo models. The group have used the gene targeting method called recombineering to generate conditional and global gene knockout mouse lines. The knockout line serves as an excellent tool to dissect the detailed functional roles of Ormdl3 and has successfully been used collaboratively with Professor Clare Lloyd’s expertise in in vivo models for asthma.
- The second area of research being conducted is as a result of original work resulting in the positional cloning of PHF11 and its association with Immunoglobulin E. Collaborating with Dr David Fear at King’s College London, the group has applied genomic approaches to dissect out the genes involved in Class Switch Recombination (CSR) and IgE production. Novel genes not previously recognised to have a role in CSR have been identified, and are the basis of future studies.
Researcher: Dr Youming Zhang
Genetics and Genomics of Cancer and Inflammation
The group are interested in the molecular basis of cancer and complex inflammatory diseases with the long-term goal of identifying novel targets for treatment. Our studies in cancer currently focus on the molecular genetic and genomic alterations that lead to mesothelioma (in collaboration with Professors Bill Cookson and Miriam Moffatt). Mesothelioma is a highly aggressive malignancy associated with asbestos exposure. It originates from mesothelial cells lining the body cavities and the pleura are the most commonly affected area.
In collaboration with researchers at the University of Miami and Moorfields Eye Hospital the group also studies molecular alterations leading to uveal melanoma and the specific changes that lead to metastasis. We have identified two of the major genetic drivers of uveal melanoma as BAP1 and SF3B1. Additionally we have observed BAP1 mutations in 30% of mesotheliomas and are performing functional studies to determine its role in tumourigenesis and metastasis.
Rare lung cancers such as pleiomorphic adenocarcinomas, thymic epithelial cancers are also an interest of the group. With researchers at the Royal Marsden Hospital, we are investigating the molecular alterations responsible for metastasis of colorectal cancers to the lung.
The group’s studies on inflammatory diseases concentrate on the genetic basis of psoriasis and psoriatic arthritis. We identify common and rare genetic changes that lead to these diseases and then investigate at their functional consequences. In collaboration with Dr Stephen Ley at the Francis Crick Institute we are examining the functional consequences of mutations in CARD14 that we showed previously lead to psoriasis, and we are developing murine models that mimic the human disease.
Researcher: Professor Anne Bowcock
Genome Technology and Systems Biology
The group are applying cutting edge genomic methods to understand epithelial development, differentiation and regeneration. In collaboration with Professors Bill Cookson and Miriam Moffatt, they are investigating the transcriptome and transcriptional regulation of air-liquid interface cultures of differentiating airway epithelia as a model for various respiratory disorders.
In a large series of ongoing international collaborations they are investigating the key epigenetic and transcriptional regulators of ear sensory epithelial regeneration with a view to treating deafness and balance disorders. This involves single cell transcriptomics, computational modeling and potential reprogramming strategies to restore function to inner ear sensory epithelia.
In a series of collaborative projects throughout Imperial the Lovett group are transferring their expertise in deriving comprehensive transcriptional profiles on very small cell numbers to multiple research groups including those of Professor Anne Bowcock and Professor Sara Rankin.
Researcher: Professor Michael Lovett
Molecular Genetics & Genomics
A primary motivation for the group is to discover the causes of asthma and to develop new therapies. We have conducted large scale genome-wide association studies (GWAS) of asthma that have identified all the major genes underlying the syndrome. We have shown that these genes transmit signals of damage and danger from the respiratory mucosa to the innate and adaptive immune systems. Several of these genes (TSLP, ST2, IL4) are current targets for novel asthma therapy, and genetic variants may be used to identify patients most likely to react to particular treatments.
Using epigenome wide association analyses we found the atopic (allergic) component of asthma is largely driven by activated eosinophils, providing a strong motivation for new anti-eosinophil therapeutic antibodies, together with biomarkers to select responsive patients.
Our interests in the cause of asthma led us to use DNA sequencing to investigate the lung microbiome. We were the first to show the lower airways contain a characteristic microbiome which is dramatically altered in the presence of asthma, opening new possibilities for treating the disease. With Dr Michael Cox we have built sequencing and analytical pipelines to examine bacterial, mycobacterial and fungal communities from a wide range of lung conditions, which now support many external collaborations. An important current initiative is to build a publically available sequence database and culture collection (HLMDb) of the lung microbiome, in collaboration with Dr Trevor Lawley at the Wellcome Trust Sanger Institute.
With generous support from the Asmarley Trust we have extended genomic and epigenetic studies to include lung cancer and malignant mesothelioma, in collaboration with Professor Mark Lathrop (McGill Genome Centre), Dr Sanjay Popat (Royal Marsden NHS Foundation Trust) and Professor Anne Bowcock (National Heart and Lung Institute). In 2106 we were awarded direct funding from the Department of Health to establish the National Centre for Mesothelioma Research.
We have also supported the implementation of genetic testing for lung diseases, in collaboration with Dr Debbie Morris-Rosendahl (Clinical Genetics, Royal Brompton and Harefield Trust).