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Interdisciplinary training network on the purinergic P2X7 receptor to control neuroinflammation and hyperexcitability in brain diseases.

Periodic Reporting for period 1 - PurinesDX (Interdisciplinary training network on the purinergic P2X7 receptor to control neuroinflammation and hyperexcitability in brain diseases.)

Reporting period: 2017-09-01 to 2019-08-31

Brain disorders affect ~179 million people and their families in Europe alone, with an annual cost to the taxpayer estimated at €800 billion- a greater economic burden than cardiovascular disease and cancer combined. Despite diverse etiology, overlap in clinical symptoms and comorbidities between brain disorders suggests shared pathomechanisms. In particular, increased hyperexcitability states in the brain driven by glial activation and neuroinflammation appear near ubiquitous. Accordingly, targeting these mechanisms may offer the potential to ameliorate symptoms and reverse disease progression across a broad span of brain disorders. Functioning as a gatekeeper to neuroinflammation and mechanistic link between neuronal hyperexcitability and glial activation, the ATP-gated, ionotropic purinergic P2X7 receptor (P2X7R) offers the most promising target for pharmacological intervention in the neuroinflammation-hyperexcitability pathway, to date. With breakthroughs in understanding P2X7R function, highly promising effects demonstrated for antagonists in models of brain disease and vast investment in P2X7R-related drug development programmes, now is the perfect time to pool resources.
PurinesDX brings together global leaders in translational research in purinergic signalling, Europe’s leading clinical specialists in a broad range of brain diseases, and industrial partners specializing in drug and biomarker development. Sharing unique genetic tools, newly developed diagnostic devices and novel, selective and brain-stable P2X7R antagonists, the synergism facilitated within PurinesDX will extend to the training of an urgently needed new generation of highly skilled, innovative, creative and entrepreneurial scientists. Alongside the provision of this interdisciplinary, international and intersectoral environment, an original and high level training in state-of-the-art neuroscience will be provided, nurturing a cohort of highly competitive researchers with potential to drive a new era of neuroscience research.
The specific PurinesDX aims are:
(i) Determine P2X7R function and cellular and sub-cellular expression across brain diseases (WP1)
(ii) Establish the cell-specific effects of increased P2X7R activity on disease pathology and determine the impact of pharmacological targeting of P2X7R on disease progression in diseases of the brain (WP2)
(iii) Identify P2X7R signature and purine metabolites as disease risk and biomarker-based diagnostics of brain diseases (WP3)
PurinesDX research activities are grouped into three work packages (Work Packages 1-3). In WP1, P2X7 expression and function has now been analysed in an array of brain diseases and data for Alzheirmer’s disease has recently been published (Martínez-Frailes C et al. (2019) Front Cell Neurosci 13:143). In addition, evidence of P2X7 altered function during brain disease has also been established (e.g. novel splice variants during Huntington’s disease).
In WP2, data from the consortium shows the potential of P2X7 as a drug target for the treatment of brain diseases, specifically in Amyotrophic Lateral Sclerosis (ALS) and drug-refractory epilepsy. In WP3, good progress has also been made in establishing potential new diagnostic tools based on P2X7 down-stream signalling including blood purines and inflammatory markers such as P2X7-dependent cytokines
In parallel with the research developed by PurinesDX ESRs, a tailored training programme was implemented, covering basic, transferable and specific skills relevant to the research fields addressed in PurinesDX. Five network-wide courses have been organised to date with a comprehensive range of theory and hands-on technical workshops to interactive soft skills courses.
The activities of the consortium were communicated as appropriate on social media channels (Twitter, Facebook) and international conferences. Of note, PurinesDX ESRs have been actively engaged in outreach from online presence to face-to-face activities.
The therapeutic potential of P2X7 antagonists has been validated across different models of brain disease, confirming our initial hypothesis of P2X7 being a common drug target.
P2X7 antagonists have been proven to be of potential therapeutic use in various pre-clinical models of different brain diseases including ALS, Alzheimer’s disease and epilepsy. During the coming year, we will clarify the impact of P2X7 antagonisms on the remaining brain diseases and determine the exact P2X7 signature in the brain and in the blood. Demonstrating the interest our research has generated among our industry Partners, Janssen Research (Partner Organization) will provide the consortium with their newest developed P2X7 antagonists which has been proven to be safe in humans and which potentially can be applied to patients in the near future.
The PurinesDX programme is targeting the shortage of researchers with adequate qualifications, skills and experience in Neuroscience. By combining input from researchers and clinicians with expertise in different brain diseases (e.g. epilepsy, schizophrenia with industrial leaders with similar interests in pharmaceuticals, biotechnology, and biosensors, the training programme is paving the way for the development of a new cohort of creative, entrepreneurial and innovative neuroscientists.
This goal is being addressed by implementing innovative individual research projects, which are training the ESRs in the latest state-of-the-art methods in neuroscience in a rapidly expanding research field. The training programme is further strengthened by a comprehensive inter-sectoral exposure, substantially involving the non-academic sector (industry and clinic). These secondments broaden the researchers’ ability to work on complex problems in existing and future cross-disciplinary research adding to their employability. As projects evolved, training opportunities beyond those forecasted in the proposal were identified and complementary research interactions branched from original projects. It is also noteworthy that this impact extended beyond individual projects to benefit participating principal investigators and organisations.
PurinesDX Annual Meeting II