PNRR mission 6 projects

Role of dietary lipids in the intestinal fibrotic processes associated to Crohn disease

Principal investigator: Alessandro Armuzzi | Partners: Azienda Ospedaliero-Universitaria di Cagliari

Crohn’s disease (CD) is a lifelong and debilitating chronic inflammatory multisystem disease leading to organ damage and impaired quality of life. More than 50% of CD patients develop a penetrating or stricturing disease due to fibrostenotic lesions, that often requires surgical intervention, as no antifibrotic treatments are currently available. What factors contribute to fibrogenesis processes remain unknown. The project aims to:

• evaluate the risk of surgery due to intestinal fibrosis in patients exposed to a high-fat diet as compared to patients exposed to a non-high fat diet;
• unravel the cellular and molecular mechanisms by which lipids promote intestinal fibrogenic process;
• evaluate the efficacy of a nanoparticle-based therapy in inhibiting the pathogenic processes induced by lipids.

A multiomics approach to identify signatures of response and resistance to immunotherapy in R/R Diffuse Large B-cell Lymphoma

Principal investigator: Carmelo Carlo Stella | Partners: Fondazione IRCCS Istituto Nazionale Tumori Milano; IRCCS Azienda Ospedaliero-Universitaria di Bologna; IRCCS Istituto Tumori Giovanni Paolo II

Novel immunotherapies have recently enriched the therapeutic armamentarium for relapsed/refractory (R/R) Diffuse Large B-cell Lymphoma (DLBCL). However, 50% of R/R DLBCL fail chimeric antigen receptor (CAR) T-cells and bispecific antibodies and represent an unmet medical need. The translational project is based on a personalized multi-omics approach to identify biomarkers of response and mechanisms of resistance. To profile high-risk patients and disease heterogeneity, researchers will genotype circulating tumor DNA and perform transcriptional analysis of circulating immune cells to profile subset signatures and T-cell receptor repertoires, integrating omics data with advanced imaging to identify high-risk signatures and design mutational-guided, individualized therapeutic programs.

Dissecting emerging original immune circuits in gastrointestinal malignancies to foster immune-based strategies

Principal investigator: Cecilia Garlanda | Partners: Azienda Ospedaliera Universitaria Federico II; Fondazione Policlinico Universitario Campus Biomedico

Immune mediators play a critical role in colorectal cancer (CRC). However, immunotherapy approaches have been successful only in a restricted group of CRC patients. Myeloid cells have opposing roles in cancer, being either protumoral or mediating anticancer responses. Their interaction with unconventional lymphoid cells (ULCs), including natural killer cells, innate lymphoid cells, and gamma-delta T cells, is poorly investigated. The applicants have provided seminal contributions in the dissection of regulatory mechanisms impacting on the functional activation of myeloid cells and ULCs in cancer. The project objective is to dissect these innovative regulatory pathways in the cross-talk between antigen-presenting cells or neutrophils and ULCs, both in preclinical models and in human biospecimens of CRC, with the final aim of identifying new potential immunotherapy options for CRC.

Prevention of post mEniscectomy osteoarthritis: from new Animal model to patient pRofiLing

Principal investigator: Elizaveta Kon | Partners: Istituto Ortopedico Galeazzi Ortopedia Rigenerativa e Ricostruttiva; Azienda ospedaliero-universitaria di Sassari; Università degli Studi di Bari Aldo Moro

Degenerative meniscal tears are the most common type of meniscal lesion and their key role in knee osteoarthritis induction and progression has been extensively demonstrated. Huge efforts have been made to identify therapeutic strategies able to slow down if not reverse the progression from meniscal degeneration to knee osteoarthritis, but two problems still need to be addressed: i) the lack of evidence of clinical, morphological, radiological parameters and transcriptomic markers linked to different degrees of risk of OA progression after meniscectomy, ii) the lack of an accurate animal model of meniscal degeneration, that could be used to evaluate different therapeutic strategies. The project aims at the development and validation of an accurate animal model of meniscus degeneration, as well as to the identification of profiling markers of patients on high risk of OA progression after meniscectomy.

Single cell dissection of the tumor microenvironment in bladder cancer for the identification of predictive tools and new therapies

Principal investigator: Massimo Lazzeri | Partners: Istituto Nazionale per lo Studio e la Cura dei Tumori Fondazione “G. Pascale”

Muscle-invasive disease (MIBC) is associated with a high mortality and no cure is available. Radical cystectomy (RC) may be applied to therapy resistant non muscle invasive BC (NMIBC) and represents the therapy of choice for MIBC, but is highly disabling. Immunotherapies, including Natural Killer (NK)-based approaches, hold strong promise in advanced BC but need to be improved to gain efficacy. Preliminary data from the Consortium indicate that the TME strongly varies between MIBC and NMIBC. Also, the consortium identified the CXC12-CXCR4 axis as a strategy to improve the efficacy of NK-cell therapies in urogenital cancers. The project will evaluate a single cell-based multidisciplinary approach to unveil the dynamics of the TME in BC during progression and in resistance to therapy, with the final goal of developing new prognostic and predictive markers.

Rescuing the function of Trem2 variants associated with Alzheimer’s Disease via a novel class of small molecules

Principal investigator: Michela Matteoli | Partners: Consiglio Nazionale delle Ricerche; IRCCS Telese, Istituti Clinici Scientifici Maugeri

Triggering Receptor Expressed on Myeloid cells 2 (TREM2) and its soluble form (sTREM2) control microglia response and correlate with neurodegenerative diseases, such as Alzheimer’s and Parkinson’s diseases (AD, PD). The project aims to modulate TREM2 in microglia using the recently discovered family of small molecules (e.g. Sulfavant A) that trigger the receptor signaling. The results will help to decipher TREM2 functions in the microglia in AD and PD and will potentially unveil novel candidates for the treatment of these diseases.

Quantitative MRI of the spinal cord in cervical myelopathy: assessment of microstructural damage for outcome improvement

Principal investigator: Salvatore Letterio Politi | Partners Azienda Ospedaliera Universitaria Federico II

Degenerative cervical myelopathy is the most common cause of spinal cord (SC) dysfunction in adults. Current diagnostic
methods cannot properly resolve signs of damage of neural structural elements at an early stage, nor provide objective
quantification of the damage. The project will implement a feasible quantitative MRI (qMRI) study of the SC in order to depict and quantify microstructural damage in the white and gray matter of patients affected by cervical spondylosis determining several degrees of myelopathy. A correlation among clinical, imaging, morpho-functional data will be sought. This will be instrumental for a more individualized and timely therapeutic decision.

Dipeptidyl peptidase 3 and bone health: mechanistic insights and clinical assessment for fracture risk prediction in Type 2 Diabetes

Principal investigator: Cristina Sobacchi |Partners: Azienda Ospedaliera Universitaria Federico II; Fondazione Policlinico Universitario Campus Biomedico

The diagnosis of bone fragility in Type 2 Diabetes (T2D) is tricky as patients have a high risk of fragility fractures despite
normal/high bone mineral density. An important mechanism responsible for the impairment of bone strength in T2D is the oxinflammation induced by chronic hyperglycaemia. The dipeptidyl peptidase 3 (DPP3) is a ubiquitous zinc-dependent exopeptidase activating the Keap1-Nrf2 antioxidant pathway; accordingly, DPP3 knock-out (KO) mice display sustained oxidative stress in the bone tissue and skeletal defects, suggesting that DPP3 is a bone protective factor and might be involved in diabetic osteopathy. The project will investigate PP3 contribution to bone matrix composition and quality in WT and DPP3 KO mice, in basal conditions and in a high fat diet (HFD)-induced T2D model; dissect DPP3 role in energy metabolism and lineage-specific functions of osteogenic cells in vitro; and assess whether DPP3 levels identify diabetic subjects at high risk of fragility fractures.

A 360-degree view of integrated diagnostic tools for precise pancreatic cancer diagnosis and prediction of response to treatment

Principal investigator: Alessandro Zerbi | Partners: ISMETT, Politecnico di Milano

The project is a prospective, multi-centric study to develop an integrated artificially intelligence-based approach of quantitative biomarkers from radiomics analysis and metabolome to investigate factors in Pancreatic Ductal Adenocarcinoma (PDAC) patients associated with treatment success to chemotherapy and/or surgical resection.