The role of protein arginine methylation in T lymphocyte migration
Lead Research Organisation:
University of Bath
Department Name: Pharmacy and Pharmacology
Abstract
We are interested in working out the fundamental mechanisms that orchestrate the way that white blood cells recognise and migrate toward sites of tissue inflammation. This will help in the design of not only new effective anti-inflammatory drugs but also anti-cancer drugs, since the spread of various tumour cells also relies on similar migratory mechanisms.
A family of molecules referred to as chemokines act as ‘homing beacons’ and direct cells to the site of tissue injury where they are required to fight infection or respond to tissue injury.
When the resolution of inflammation is impaired and/or the inflammatory response is switched on inappropriately, cells accumulate in tissues unnecessarily, leading to a range of inflammatory or autoimmune diseases.
Biochemical signals within cells convey information that allow cells to move in response to chemokines and provide a sense directionality. Professor Ward has uncovered new evidence that addition of so-called methyl groups to proteins could be an important mechanism for cell migration.
We plan to use a combined molecular and chemical approaches that provide the most powerful way to control and learn about individual methylated proteins within cells and organisms. Ultimately, the chemicals and information that we obtain may be combined for future development of new drugs that may block unwanted cell migration.
A family of molecules referred to as chemokines act as ‘homing beacons’ and direct cells to the site of tissue injury where they are required to fight infection or respond to tissue injury.
When the resolution of inflammation is impaired and/or the inflammatory response is switched on inappropriately, cells accumulate in tissues unnecessarily, leading to a range of inflammatory or autoimmune diseases.
Biochemical signals within cells convey information that allow cells to move in response to chemokines and provide a sense directionality. Professor Ward has uncovered new evidence that addition of so-called methyl groups to proteins could be an important mechanism for cell migration.
We plan to use a combined molecular and chemical approaches that provide the most powerful way to control and learn about individual methylated proteins within cells and organisms. Ultimately, the chemicals and information that we obtain may be combined for future development of new drugs that may block unwanted cell migration.
Technical Summary
This proposal describes a ?proof-of concept? pilot strategy to probe the functional importance of protein methyl arginine transferases and assess whether this post-translational event is receptor regulated. We envisage that chemical interference represents the most appropriate means of characterising the dynamic role of this protein class (for example in T lymphocyte migration) and therefore seek to evaluate rationally designed chemical inhibitors. We recognise that there may be opportunities for new therapeutic interventions in a range of diseases. At the end of this study, we will be well placed to embark on a programme of research to set out to characterise the role of the PRMTs and fully exploit targeting of this pathway. We therefore aim to:
(i) Explore the hypothesis that arginine methylation is a receptor regulated event in the response of T lymphocytes to chemokines.
(ii) Address the significant paucity of potent small molecule pharmacological tools directed against protein arginine methyltransferases and amenable to rational improvement.
(i) Explore the hypothesis that arginine methylation is a receptor regulated event in the response of T lymphocytes to chemokines.
(ii) Address the significant paucity of potent small molecule pharmacological tools directed against protein arginine methyltransferases and amenable to rational improvement.
