New interventional approaches on multiple inflammatory pathways involved in regeneration after trauma and aging- associated diseases

The translational regulation has a critical role in controlling appropriate gene expression during the inflammatory response and, thereby, is a new biologically relevant cellular mechanism to respond to rapid changes in the microenvironment or to serve specific functions. Altered expression or functions of the various components of the translational machinery have been linked to several pathologies in the central nervous system (CNS), affecting important processes in the brain, such as neurogenesis. Therefore, many therapeutic approaches have been developed to avoid or mitigate the deleterious effects caused by the chronic immune response activation. Stress and stress hormones, glucocorticoids (GCs), exert widespread actions in CNS, and chronic stress, and elevated GC levels, are linked to mood disorders, traumatic events and neurodegenerative disorders, such as Alzheimer's (AD). Preclinical studies have shown that GCs exert a neuroprotective effect by modulating the immune responses after injury. According to these data, GCs play a crucial role in providing neuroprotection after ischemic stroke and other acute CNS injuries. GCs are the most useful anti-inflammatory compounds, but they are problematic since their long-term administration causes detrimental side effects. Therefore, new drugs substituting GCs are needed. Considering the complex molecular networks that characterize these pathologies, there is a growing consensus that a single-target pharmacologic approach is inadequate due to the multifactorial nature of such diseases. Therefore, a better understanding of the cross-talk between RACK1, ADAM10 and GILZ, important genes involved in inflammation, as well as the contribute of CBS/H2S-L-serine- S1P/NO pathways, to modulate the inhibition vs the stimulation of neurogenesis during neuroinflammation (NI), could help to develop novel anti-inflammatory approach with a potential application in neurodegenerative and traumatic diseases with a strong inflammatory component. The project will be divided in two main branches. On one hand, by using GILZ-Tg mice that overexpress GILZ, GILZ influence in the progression of CNS injuries [spinal cord (SCI) and brain trauma (TBI)] and AD will be studied, evaluating the interaction with other inflammatory genes (RACK1 and ADAM10) as well as the influence on H2S production. On the other hand, TBI, SCI and AD mice will be treated with H2S donors and GILZ-based and ADAM10 targeting peptides to identify the best treatment(s) to modify the progression of these diseases. The expected results will provide a full picture of the effects of the manipulation of ADAM10 pathway on synapse failure, NI and neurogenesis in AD and will disclose the potential role of ADAM10, GILZ, RACK and H2S network in such pathological events. Our data will lay the ground for the development of therapeutic tool effective as GC and mimicking the anti-inflammatory/immunosuppressive properties, but with minor adverse events