Shh Signaling in Brain AVMs: Novel Player & Therapeutic Target

The present study, entitled "SHAM Study," is a prospective observational translational study aimed at investigating the molecular mechanisms underlying brain arteriovenous malformations (AVMs). In particular, the study seeks to explore the role of the Sonic Hedgehog (Shh) signaling pathway, which has recently been hypothesized as a potential key player in pathological angiogenesis and in the maintenance of the malformative nidus. The study will be conducted through the analysis of brain tissues obtained exclusively as residual material from neurosurgical procedures performed for clinical indications. Under no circumstances will additional procedures be carried out or modifications made to the patients' therapeutic pathway for research purposes. Samples will include tissues from adult patients undergoing AVM resection and, as controls, non-pathological brain tissues derived from surgeries performed for other indications, such as drug-resistant epilepsy. The methodological approach involves the isolation of endothelial cells from collected samples and their characterization using multi-omics techniques, including transcriptomic analysis, microRNA profiling, and quantitative proteomics. The resulting data will be integrated through advanced bioinformatics analyses in order to identify specific molecular patterns, altered pathways, and potential biomarkers. Particular attention will be given to the evaluation of Shh pathway activation and its interactions with other signaling systems involved in AVM pathogenesis. The collected biological material may also be used, subject to specific informed consent, for preclinical studies conducted on animal models, with the aim of further investigating the identified pathogenetic mechanisms and assessing their functional relevance. Such activities will be carried out in compliance with current regulations on animal experimentation and subject to approval by the relevant authorities. The primary objective of the study is to ident