FRRB Project 3433068 - Linking inflammation to progression of neurodegeneration in Parkinson's disease
The Coordinator of the project is IRCCS Fondazione Istituto Neurologico Nazionale Casimiro Mondino. The Lead Principal Investigator of the project is Prof. Antonio Pisani.
|Project Start Date:||May 1, 2023|
|Project End Date:||April 30, 2026|
|Project Partners:|| - IRCCS Fondazione Istituto Neurologico Nazionale Casimiro Mondino
- Università degli Studi di Milano
- IRCCS Istituto Clinico Humanitas – Humanitas Mirasole S.p.A.
Parkinson’s disease (PD) is a neurodegenerative disease with multiple mechanisms involved and different progression rate. Unmet needs in the field include the availability of accurate biomarkers and disease-modifying drugs. Here, we designed a translational study to investigate the role of inflammation in neurodegeneration. Nrf2-mediated inflammation will be evaluated as a pathophysiological index, representing a putative progression biomarker and drug target. The clinical group will recruit PD patients at different stages, and by performing extensive biochemical characterization from PBMCs and plasma, will generate multiple biomarkers to define predictors for disease progression. The preclinical branch will use the a-synuclein preformed fibrils (a-syn-PFF) mouse model to evaluate disease progression from early to late stages. A combination of imaging, biochemistry, molecular biology and behavioral assays will be used to evaluate the role of Nrf2 and the therapeutic efficacy of Nrf2 activators. Of note, mice studies will be paralleled by the use of 3D human organoids exposed to a-syn-PFF as new model of synucleinopathy to identify Nrf2 molecular targets. Altogether, our project will leverage the information derived from clinical evaluations and state-of-the-art rodent and 3D human cellular models to characterize the role of Nrf2-mediated neuroinflammation and facilitate the drug repurposing of Nrf2 modulators to gain a rapid transferability to patients’ unmet needs.