Project ID CM-HD2023_38

ThemeCM-HD

Co Supervisor 1A Cancer and Pharmaceutical Sciences CAG: Pharmaceutical Sciences; Allergy and RespiratoryWebsite

Co Supervisor 1B Cancer and Pharmaceutical Sciences CAG: Pharmaceutical SciencesWebsite

The nucleotide ‘halo’ in inflammation: biased P2Y1 platelet signalling differentially regulates inflammation and haemostasis.

Platelets are requisite for inflammation and host responses to infections. Platelets represent novel cellular targets from which we can control diseases such as asthma and COPD, or infections such bacterial or viral induced Pneumonia or COVID-19, for which society needs more efficacious anti-inflammatory drugs. Our current research has established that the inflammatory actions of platelets are controlled via biased-signalling of the P2Y1 receptor (we have synthesized novel biased antagonists, and discovered endogenous nucleotides with biased properties compared to ADP and ATP). Within the milieu of this nucleotide ‘halo’, we need to understand how biased-P2Y1 signalling determines platelet function, and overrides activity leading to thrombosis as we validate biased-P2Y1 antagonists as a novel anti-inflammatory therapeutic target.

Aim of the project: To define how competing functions of platelets are controlled by a nucleotide ‘halo’ to determine biased and classical P2Y1 signalling, using allergic inflammation as a model context.

Objectives:
1. Year 1. Microscopy, flow-cytometry, cell signalling assays; and in vivo skills to set up a murine model of allergic lung inflammation and/or infection. Characterization of changes to the nucleotide ‘halo’ in the lung and platelet signalling events. In silico modelling to study interactions of biased-nucleotide agonists with binding site residues.
2. Year 2. Skill sets will be expanded to in vitro cell harvesting, platelet functional assays applicable to haemostasis and inflammation, to determine the significance of various biased-P2Y1 activities on platelet function.
3. Year 3 and 4. Determine how biased-P2Y1 activation of platelets modulates inflammation and haemostasis in a murine model of allergic lung inflammation.

One representative publication from each co-supervisor:

• Shah SA, Kanabar V, Riffo-Vasquez Y, Mohamed, Z, Cleary SJ, Corrigan C, James AL, Elliot JG, Shute JK, Page CP, Pitchford SC. Platelets independently recruit into asthmatic lungs and models of allergic inflammation via CCR3. Am J Respir Cell Mol Biol. 2021; 64:557-568

• Picconi, P., Hind, C. K., Nahar, K. S., Jamshidi, S., Di Maggio, L., Saeed, N., Evans, B., Solomons, J., Wand, M. E., Sutton, J. M., and Rahman, K. M. (2020) New Broad-Spectrum Antibiotics Containing a Pyrrolobenzodiazepine Ring with Activity against Multidrug-Resistant Gram-Negative Bacteria, Journal of Medicinal Chemistry 63, 6941-6958.