Julian Knight group

Research projects

Current research efforts are focused on the following areas:

1. Mapping genetic modulators of innate and adaptive immunity.

Cells
Exploring context specificity

Recent GWAS have highlighted the extent of association for autoimmune, infectious and inflammatory diseases and we aim to map regulatory genetic variants modulating gene expression in a variety of cellular contexts relevant to disease. We have analysed gene expression as a quantitative trait in different primary immune cell populations and conditions, demonstrated that a high degree of context specificity exists and used this data to help resolve regulatory variants from GWAS signals.

We are extending this work to resolve regulatory variants in different environmental contexts relevant to disease risk including extreme response to endotoxin. We are also continuing our efforts to understand the functional significance of disease-associated genetic variation involving the major histocompatibility complex (MHC).

2. Defining causal variants in a disease context.

We complement our work using model systems and analysis of cells from healthy volunteers with patient focused collaborative studies involving clinical samples. This includes autoimmune disease (GENExpressID study) together with common and rare causes of severe infection.

Ankylosing spondylitis: we work with Professor Paul Bowness, Professor Paul Wordsworth and Professor Matt Brown to investigate genomic and epigenomic determinants of ankylosing spondylitis. A major programme funded by Arthritis Research UK is taking forward this research by recruiting patients for functional genomic profiling and integrating with GWAS.

Sepsis: we work with Professor Charles Hinds, Professor Adrian Hill and the GAinS Investigators to use functional genomic approaches to understand heterogeneity in patients with severe sepsis admitted to intensive care. Transcriptomic profiling has defined a small panel of genes that can inform individual sepsis response state.

Editing
Establishing mechanism

Rare severe infections: We complement analysis of common infectious diseases by collaborative work investigating rare primary immunodeficiency disorders (Dr Smita Patel) and severe invasive Streptococcal infection (Dr Tom Parks).

Other collaborative studies: population genetics and functional genomics in Emirati population with type II diabetes (Professor Houman Ashrafian); genetics of epilepsy (Professor Houman Ashrafian, Professor Zuberi Sameer and Dr Joe Symonds); and immunology of epilepsy (Dr Arjune Sen and Dr Sarosh Irani).

3. Integrative approaches and target prioritisation.

Integrative_analysis

We are using a genetics-led approach to define genes and pathways responsible for observed genetic associations in GWAS.

This involves use of functional genomic profiling and integrative analysis to understand mechanism using in house and publically generated tools and resources.

The goal is to enhance the utility of human genetics for understanding disease pathogenesis and novel therapeutic targets.  

Thsi work is being carried out as part of the Unrestricted Leveraging of Targets for Research Advancement and Drug Discovery (ULTRA-DD) Innovative Medicines Initiative with the Structural Genomics Consortium and pharma partners.