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Description
Osteoarthritis is a multifactorial chronic disease that nowadays represents a leading cause of disability and source of social costs. This syndrome arises from imbalanced repair and destruction of joint tissues, where pro-inflammatory mediators favor an exacerbated osteoclast activity. The infiltration of T cells in the synovial fluid and their interplay with osteoclasts contribute greatly to this degenerative joint disease and are the focus of this proposal. In recent years, the proponent laboratories help lead to the recognition of central enzymes of the glycerophospholipid metabolism, diacylglycerol kinases and secreted phospholipases A2, as determinants in T-cell and osteoclast functions, respectively. We propose to build up on this expertise to assess the involvement of these glycerophospholipid-metabolizing enzymes in the cross talk between human osteoclasts and T cells, with the final aim to identify regulatory mechanisms of therapeutic relevance to limit bone loss. In detail, genetic and pharmacological blockage of diacylglycerol kinases will be instrumental to evaluate their role in T-cell recruitment by osteoclast-derived chemokines, activation at the osteoclast immunological synapse, and regulation by osteoclast-secreted cytokines. In search of novel immunomodulatory strategies, we also propose a virtual and biochemical screening of DGKa activating compounds starting from available templates. Those studies aim to clarify how osteoclasts affect diacylglycerol metabolism in T cells, and the impact on T-cell activity and T-cell mediated regulation of osteoclast activity. On the other hand, the role of secreted phospholipases A2 will be deepened in the human osteoclastogenesis process, with prominent relevance for the still enigmatic osteoclast cell-cell fusion process, and in the osteoclast – T-cell cross communication, both crucial players in the onset of bone pathologies. Genetic reduction of protein expression, together with inhibitors with distinct selectivity, and recombinant proteins (wild-type or catalytically inactive forms, full-length or partial protein sequences) will aid in dissecting out secreted phospholipase A2 involvement and mechanism of action, as well as lipidomic studies for the identification of lipid signaling mediators. The proposed investigation will contribute to the current knowledge on the osteoclast – T-cell interplay, with the final aim to identify strategic targets for efficacious therapeutic intervention in diseases with osteoclast dysfunction, such as osteoarthritis.
Stato | Attivo |
---|---|
Data di inizio/fine effettiva | 30/11/23 → 29/11/25 |
Funding
- MUR - Ministero dell'Università e Ricerca
Obiettivi di sviluppo sostenibile dell’ONU
Nel 2015, gli Stati membri dell'ONU hanno sottoscritto 17 obiettivi globali di sviluppo sostenibile (OSS) per porre fine alla povertà, salvaguardare il pianeta e assicurare prosperità a tutti. Il presente lavoro contribuisce al raggiungimento dei seguenti OSS:
Keywords
- osteoarthritis
- phospholipase A2
- diacylglycerol kinase
- osteoclast
- T cell
- signal transduction
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