Periodic Reporting for period 1 - PIANO (Nanoparticle-Based Imaging and Therapy of Chronic Pain in the Dorsal Root Ganglia (DRG))
Periodo di rendicontazione: 2021-03-01 al 2023-02-28
Chronic neuropathic pain, which results from peripheral nerve damage and chemotherapy-induced neuropathy (CIPN) remains a clinical challenge. Since current pain killers are only partially effective and bring severe side effects, there is urgent need for novel therapies.
PIANO proposes to target neurons and/or immune cells in the dorsal root ganglia (DRG), which are located outside the CNS, to improve pain treatment and monitor changes in DRG under neuropathic pain conditions.
PIANO aims to delineate novel pathways and identify strategies to target both sensory neurons and macrophages in DRG since these contain the cell bodies of specialised neurons that transmit noxious signalling from the periphery to the central nervous system, where pain is perceived. Indeed, PIANO research programme includes 4 work packages which are connected in their aims i) to unravel mechanisms involved in pain signalling and inflammatory processes, ii) synthesise compounds that will inhibit pain-neuron activity, and iii) develop targeted nanoparticles to enable sensory neuron visualisation and deliver analgesic compounds.
PIANO proposes to target neurons and/or immune cells in the dorsal root ganglia (DRG), which are located outside the CNS, to improve pain treatment and monitor changes in DRG under neuropathic pain conditions.
PIANO aims to delineate novel pathways and identify strategies to target both sensory neurons and macrophages in DRG since these contain the cell bodies of specialised neurons that transmit noxious signalling from the periphery to the central nervous system, where pain is perceived. Indeed, PIANO research programme includes 4 work packages which are connected in their aims i) to unravel mechanisms involved in pain signalling and inflammatory processes, ii) synthesise compounds that will inhibit pain-neuron activity, and iii) develop targeted nanoparticles to enable sensory neuron visualisation and deliver analgesic compounds.
We made significant progress in the formulation of nanoparticles to target macrophages and either promote shift in phenotype/death or enable macrophage imaging. We started with the development of biomaterials to target sensory neurons and advance our understanding of TRPV2 channel pore-dynamic landscape and synthesis of specific TRV2 modulators. We are delineating mechanisms by which M1-macrophages release EVs that are taken-up by nociceptive neurons to influence neuronal activity and mechanisms by which GABA inhibits DRG neuron activity. In this context, we are developing chemical technologies that will enable mechanistic studies to identify disease-relevant populations of macrophages and exploit macrophage ablation as a novel therapeutic approach for analgesia. We have started to elucidate possible function of sensory neuron expressed receptors, namely TRPV1, TRPM8, and TRPA1, in detection of thermal and chemical stimuli in paclitaxel induced neuropathic pain. We started to develop novel pain-relieving agents which block TRPV1 and Nav1.7 channels and are endowed with a safer profile compared to current therapeutic options.
PIANO focuses on neuron and immune cell activities in dorsal root ganglia which are associated with neuropathic pain. Our innovative aims are to inhibit pain-neuron activity with channel blockers and target macrophages with nanoparticles that would promote polarisation towards M2-anti-inflammatory phenotype. The results obtained by the end of the project will be of interest to scientists working in neuroinflammation and chronic pain with a special focus on nanoparticle selective delivery to target cells. In addition, data will be of interest to clinicians who treat people with neuropathic pain and to pharmaceutical companies interested in developing better analgesics for treating chronic pain.