BANDI A CASCATA
Severe Infections and Sepsis clinical NEtwork for identification of clinical and diagnostic Markers, immunological monitoring and “Target and tailored” therapies for adults, children and patients admitted to intensive care units - SIS – NET
Finanziatore: MUR
Responsabile Scientifico: Edoardo DE ROBERTIS
Finanziamento: € 205.000
Durata: 2023-2025
Infections caused by multidrug-resistant bacteria and fungi, alongside the emergence and re-emergence of viruses and other highly contagious diseases, pose significant challenges in clinical and organizational settings. The necessity for multi-center networks has become evident, enabling precise epidemiological surveillance and interdisciplinary research initiatives to deliver swift and effective responses. This project seeks to address the absence of a network capable of identifying markers and monitoring severe infections and sepsis caused by community and hospital-acquired pathogens in individuals across all age groups, including those in intensive care units. The primary goal is to establish a national network that facilitates resource-sharing and data exchange for the identification and monitoring of severe infections and sepsis from both community and hospital-acquired pathogens, aligning with the objectives of the INF-ACT research program. The project will encompass five work packages, focusing on establishing a national network comprising adult and neonatal intensive care units, infectious disease and pediatric departments, microbiology laboratories, and designing multi-center registries for descriptive observational and diagnostic-prognostic evaluations. Furthermore, the project will involve analyzing collected data to generate regular clinical reports, exploring associations between clinical diagnostic markers, immunological indicators, disease severity, and outcomes. This will lead to the development of tailored therapy protocols based on clinical profiles. Ultimately, the project aims to drive scientific progress, enhance the country's scientific reputation from a multidisciplinary perspective, and foster collaboration among participating institutions to ensure the successful implementation of the outlined objectives.
Advanced Strategies for Assessing and educating immune responses to Gene Therapy
Finanziatore: MUR
Responsabile Scientifico: Francesca FALLARINO
Finanziamento: € 70.000
Durata: 2024-2025
Gene Therapies (GT) are innovative treatments for numerous diseases, with several gene products recently receiving marketing approval also in Hemophilia treatment. However, the host immune response to the administered vectors, and transgenes remains a major limitation, as the key signaling pathways regulating this response are unknown. Hemophilia A (HA), a hemorrhagic disease caused mainly by mutations of the F8 gene, is intensively treated with proteins and GT and represents an ideal model to address these issues. One of the most difficultcomplications is the development of inhibitory alloantibodies against the infused FVIII protein, an immune response against viral vectors and the F8 transgene according to GT. Re-educ8 aims to unravel the intra - and intercellular signaling synergies involved in immune tolerance to the successful and durable FVIII gene therapies by taking advantage of innovative vector tools and preclinical in vivo models developed by the applicant and collaborators in this proposal. Re-educ8 aims to: 1. improve knowledge of the mechanisms of immune tolerance and use this knowledge to optimize GT and protein therapy that works better than existing. 2. identify biomarkers in preclinical models of the immune and vascular systems that will enable a personalized approach to preclinical testing and therapeutic regimens. If even partially successful, the project will provide a roadmap to advance both basic and translational knowledge of the key molecular and cellular determinants of immune responses gene replacement therapies for HA.
Development of anti-super-enhancer of chemokines siRNAs engineered Nanocarriers for treatment of human Fibrotic disorders “NANOFIB”
Finanziatore: MUR
Responsabile Scientifico: Stefano FIORUCCI
Finanziamento: € 615.000
Durata: 2023-2025
Summary:The project is to design specific nanocarriers able to carry on siRNA directed against multiple chemokines simultaneously and more specifically to target super enhancers that regulate the expression of multiple chemokines in target tissues. This approach takes into consideration the broad and redundant nature of the chemokine pathway, where eliminating a single chemokine may prove ineffective and potentially enhance other signaling pathways. Specifically we aim to design and test nanocarriers loaded anti siRNA directed against the Bromodomain and Extraterminal (BET) proteins that regulate the expression of multiple chemokines. This approach is expected to result in the simultaneous down-regulation of multiple chemokines and therefore, to avoid or reverse macrophages-directed fibroblasts activation in tissues. The goal of this project is to develop a biological screening platform to tackle fibrotic diseases with engineered nanocarriers. Specifically we aim to design and test engineering nanoparticle loaded siRNA able to reprogram the macrophages-dependent activation of fibroblasts in fibrotic disorders of liver, intestine and lung. One of the key aspects in implementing siRNA therapy is the identification of target genes, the modulation of which will results in an effective reduction of fibrosis. For target identification we have carried out a series of preliminary investigations on RNAseq repositories of A) healthy and cirrhotic liver samples (Graupera I. et al -Molecular characterization of chronic liver disease dynamics: from liver fibrosis to acute-on-chronic liver failure deposited under the code GSE139602); B) intestinal fibrosis; C) lung fibrosis from IPF patients (Barrett T, et al. Ncbi geo: Archive for functional genomics data sets–update. Nucleic Acids Res (2013) 41(Database issue):D991–5. doi: 10.1093/nar/gks1193) and D) our own murine models of liver fibrosis induced through the administration of carbon tetrachloride (CCl4) to wild type mice (the data has already been published and deposited with the DOI: 10.17632/3xvs65zmhm.1). From these studies, it appears that the most up-regulated genes in fibrosis across various human settings and murine models, are chemokines and their receptors. The mechanistic potential of chemokines and their receptors in the development of tissues fibrosis across various organ has been extensively validated by in vitro studies as well as genes knockout.
DECRYPTING THE SYMBIONTS-VECTORS-PATHOGENS TRILOGY: NEW EFFICIENT TOOLS FOR MONITORING AND CONTROL “SYMPATHRY”
Finanziatore: MUR
Responsabile Scientifico: Roberta SPACCAPELO
Finanziamento: € 208.000
Durata: 2023-2025
Summary:The aim of the proposal is to deepen our understanding of the role of microbiota-vector interactions in phenomena related to environmental adaptation, insecticide resistance and vectorial capacity of mosquitos and sand flies, vectors of several highly/potentially pathogenic viruses (Dengue, Chikungunya, Zika, Japanese Encephalitis, West Nile, Usutu virus). The current increase in temperature, frequency of extreme weather events and urbanization are favouring the expansion of invasive mosquito species, including Ae. albopictus, Ae. koreicus and Ae. japonicus. Resistance to pyrethroids has recently been reported in Ae. albopictus populations across southern Europe. Mosquito and sandfly microbiota likely influence multiple aspects of host biology, including vector competence, insecticide resistance and temperature adaption; stable bacterial symbiosis (Wolbachia) is being used as an innovative vector control tool. Planned activities of the present proposal include: ● mosquito and sandfly collection in Italy during the 2024 and 2025 warm seasons and recording of geographical coordinates/climatic variables; ● morphological and molecular identification of vector species/strains and eventual VB pathogens; ● metagenomic and pathobiomic analyses of the microbiota in relation to recorded variables, host specificity and microbial competition within specific microbiota (Asaia/ Wolbachia); ● laboratory manipulation of invasive mosquito species under varying temperatures and co-infection with pathogens to evaluate the contribution of symbionts to thermal adaptation and vectorial capacity; ● trials with a “Wolbachia-based approach” for mosquito control in restricted geographical areas of Central Italy and the study of potential competition Wolbachia vs. Asaia. Coherence to the INF-ACT research programme includes harnessing vector microbiota and pathogen interactions for novel control strategies and the production of a "cepparium" with a substantial contribution to the Biobank envisaged by Spoke-4.