Bhattacharya Group: Targeting chemokine-driven inflammation in atherosclerosis

The project will develop and characterize chemokine-inhibiting peptides tagged with “molecular ZIP codes” so that they inhibit chemokines specifically in the atherosclerotic plaque.

About the Research 

Inflammation of the atherosclerotic plaque results in rupture or haemorrhage, leading to heart attack and stroke, creating a huge disease burden. Current therapeutic approaches to limit inflammation such as canakinumab or colchicine act systemically, resulting in side-effects such as infection. Approaches to reduce immune cell trafficking to the atherosclerotic plaque may complement existing therapies such as cholesterol lowering drugs and provide significant patient benefit.

Rationale: Extensive expression, genetic and pharmacological evidence validates the chemokine network as a target in atherosclerosis. Unfortunately, anti-chemokine agents have not yet translated into clinically effective therapeutics, likely because multiple redundant pathways connect chemokines to immune cells. To develop effective therapeutics, we took our inspiration from ticks. Ticks produce proteins called evasins that inhibit multiple chemokines. Using a phage-display approach combined with multi-chemokine selection, we identified a lead 16-mer peptide (HD2) from a tick evasin that binds and inhibits several CC and CXC-class chemokines. Using combinatorial saturation mutagenesis, we identified mutations of HD2 that dramatically enhance chemokine binding. Combinatorially mutated HD2 peptides show enhanced potency in inhibiting a synthetic chemokine pool designed to represent plaque-expression of chemokines, as assessed by RNA-sequencing.

Hypothesis: We hypothesize that neutralizing multiple plaque-expressed chemokines will ameliorate atherosclerotic plaque inflammation.

Aims: Our aim is to develop novel agents that reduce immune cell trafficking to the atherosclerotic plaque by targeting the chemokine network in the plaque itself. 

Project Training: This project gives the opportunity to use a broad range of in vitro and in vivo techniques tailored to the candidate’s interest. A typical in vitro project would involve developing ZIP-code/nanobody tagged peptides/peptidomimetics using molecular cloning; expressing and purifying these from E.coli; studying their biological activity in flow-cytometry chemotaxis assays using cell lines and primary cells. An in vivo project would involve studying these ZIP-code/nanobody tagged peptides/peptidomimetics in models of disease such as air-pouch inflammation and atherosclerosis.

Training Opportunities 

The project will be jointly supervised by Shoumo Bhattacharya and Gillian Douglas, and the student will have training in both laboratories. The Bhattacharya and Douglas laboratories specialise in molecular biology, biochemistry, protein chemistry, immune cell biology, chemokine pharmacology, cardiovascular biology and animal models of cardiovascular inflammation, and are funded by a jointly held British Heart Foundation Program Grant.

Students are encouraged to attend the MRC Weatherall Institute of Molecular Medicine DPhil Course, which takes place in the autumn of their first year. Running over several days, this course helps students to develop basic research and presentation skills, as well as introducing them to a wide range of scientific techniques and principles, ensuring that students have the opportunity to build a broad-based understanding of differing research methodologies.

Generic skills training is offered through the Medical Sciences Division's Skills Training Programme. This programme offers a comprehensive range of courses covering many important areas of researcher development: knowledge and intellectual abilities, personal effectiveness, research governance and organisation, and engagement, influence, and impact. Students are actively encouraged to take advantage of the training opportunities available to them.

As well as the specific training detailed above, students will have access to a wide range of seminars and training opportunities through the many research institutes and centres based in Oxford.

The Department has a successful mentoring scheme, open to graduate students, which provides an additional possible channel for personal and professional development outside the regular supervisory framework. We hold an Athena SWAN Silver Award in recognition of our efforts to build a happy and rewarding environment where all staff and students are supported to achieve their full potential.

Additional Supervisors

1. Gillian Douglas 

Publications