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Novel Strategies To Boost Tristetraprolin Function: A Critical Anti-Inflammatory Protein In Asthma.

Project Member(s): Ammit, A.

Funding or Partner Organisation: National Health & Medical Research Council (NHMRC Project Grants)

Start year: 2016

Summary: Asthma is a chronic disorder that affects millions of people worldwide. The challenge for asthma treatment today is to identify alternative anti-inflammatory strategies with reduced side-effects. We propose a new approach to meet this challenge: our goal is to stimulate the critical anti-inflammatory protein tristetraprolin (TTP). TTP functions to induce mRNA decay of cytokines; including cytokines that have been implicated in asthma. Critically, TTP is controlled by phosphorylation, providing us with important points of regulatory control that we propose to exploit to boost TTP function. In the unphosphorylated state TTP is competent to induce mRNA decay however, this form of TTP is also subject to proteasome-mediated degradation. We therefore propose a dual approach to: (1) switch TTP to the unphosphorylated (active) state by enhancing activity of PP2A phosphatase which catalyses the dephosphorylation of the critical TTP residues; and (2) derive strategies to overcome proteasome-mediated degradation of the unphosphorylated protein. We will achieve these goals by in vitro studies in airway structural cells to identify and confirm the relevant mechanisms. We will then complement these studies by inducing allergic airways disease in mice and confirm the effects of altered TTP phosphorylation via the use of an established TTP knock-in mouse model. This project brings together a team of international experts with unique resources and expertise to address this novel hypothesis and the new knowledge gained from our research will guide future development of novel anti-inflammatory pharmacotherapeutic approaches to combat asthma.

Publications:

Nader, CP, Cidem, A, Verrills, NM & Ammit, AJ 2019, 'Protein phosphatase 2A (PP2A): a key phosphatase in the progression of chronic obstructive pulmonary disease (COPD) to lung cancer', Respiratory Research, vol. 20, no. 1.
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Bradbury, P, Traini, D, Ammit, AJ, Young, PM & Ong, HX 2018, 'Repurposing of statins via inhalation to treat lung inflammatory conditions', Advanced Drug Delivery Reviews, vol. 133, pp. 93-106.
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Moosavi, SM, Prabhala, P & Ammit, AJ 2017, 'Role and regulation of MKP-1 in airway inflammation', Respiratory Research, vol. 18, no. 1, pp. 1-12.
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Nair, PM, Starkey, MR, Haw, TJ, Liu, G, Horvat, JC, Morris, JC, Verrills, NM, Clark, AR, Ammit, AJ & Hansbro, PM 2017, 'Targeting PP2A and proteasome activity ameliorates features of allergic airway disease in mice', Allergy, vol. 72, no. 12, pp. 1891-1903.
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Patel, BS, Kugel, MJ, Baehring, G & Ammit, AJ 2017, 'Doxofylline does not increase formoterol-induced cAMP nor MKP-1 expression in ASM cells resulting in lack of anti-inflammatory effect', Pulmonary Pharmacology & Therapeutics, vol. 45, pp. 34-39.
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Patel, BS, Rahman, MM, Baehring, G, Xenaki, D, Tang, FS-M, Oliver, BG & Ammit, AJ 2017, 'Roflumilast N-Oxide in Combination with Formoterol Enhances the Antiinflammatory Effect of Dexamethasone in Airway Smooth Muscle Cells', American Journal of Respiratory Cell and Molecular Biology, vol. 56, no. 4, pp. 532-538.
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Patel, BS, Rahman, MM, Rumzhum, NN, Oliver, BG, Verrills, NM & Ammit, AJ 2016, 'Theophylline Represses IL-8 Secretion from Airway Smooth Muscle Cells Independently of Phosphodiesterase Inhibition. Novel Role as a Protein Phosphatase 2A Activator', American Journal of Respiratory Cell and Molecular Biology, vol. 54, no. 6, pp. 792-801.
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Prabhala, P, Bunge, K, Ge, Q & Ammit, AJ 2016, 'Corticosteroid-Induced MKP-1 Represses Pro-Inflammatory Cytokine Secretion by Enhancing Activity of Tristetraprolin (TTP) in ASM Cells', Journal of Cellular Physiology, vol. 231, no. 10, pp. 2153-2158.
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Rahman, MM, Prabhala, P, Rumzhum, NN, Patel, BS, Wickop, T, Hansbro, PM, Verrills, NM & Ammit, AJ 2016, 'TLR2 ligation induces corticosteroid insensitivity in A549 lung epithelial cells: Anti-inflammatory impact of PP2A activators', The International Journal of Biochemistry & Cell Biology, vol. 78, pp. 279-287.
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Rahman, MM, Prünte, L, Lebender, LF, Patel, BS, Gelissen, I, Hansbro, PM, Morris, JC, Clark, AR, Verrills, NM & Ammit, AJ 2016, 'The phosphorylated form of FTY720 activates PP2A, represses inflammation and is devoid of S1P agonism in A549 lung epithelial cells', Scientific Reports, vol. 6, no. 1, pp. 1-8.
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Rumzhum, NN & Ammit, AJ 2016, 'Prostaglandin E2 induces expression of MAPK phosphatase 1 (MKP-1) in airway smooth muscle cells', European Journal of Pharmacology, vol. 782, pp. 1-5.
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Rumzhum, NN, Patel, BS, Prabhala, P, Gelissen, IC, Oliver, BG & Ammit, AJ 2016, 'IL-17A increases TNF-α-induced COX-2 protein stability and augments PGE2secretion from airway smooth muscle cells: impact on β2-adrenergic receptor desensitization', Allergy, vol. 71, no. 3, pp. 387-396.
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Rumzhum, NN, Rahman, MM, Oliver, BG & Ammit, AJ 2016, 'Effect of Sphingosine 1-Phosphate on Cyclo-Oxygenase-2 Expression, Prostaglandin E2 Secretion, and β2-Adrenergic Receptor Desensitization', American Journal of Respiratory Cell and Molecular Biology, vol. 54, no. 1, pp. 128-135.
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Patel, BS, Prabhala, P, Oliver, BG & Ammit, AJ 2015, 'Inhibitors of Phosphodiesterase 4, but Not Phosphodiesterase 3, Increase β2-Agonist–Induced Expression of Antiinflammatory Mitogen-Activated Protein Kinase Phosphatase 1 in Airway Smooth Muscle Cells', American Journal of Respiratory Cell and Molecular Biology, vol. 52, no. 5, pp. 634-640.
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Keywords: Asthma

FOR Codes: Respiratory Diseases, Respiratory System and Diseases (incl. Asthma), Respiratory diseases , Clinical health