Anagrafe della ricerca

22q11.2 deletion syndrome (22q11.2DS) is the most common human chromosomal microdeletion, causing neurological diseases, thymus hypoplasia, hypoparathyroidism, anomalous craniofacial features, skeletal/connective and/or cardiac defects1. The pharyngeal/structural cardiac phenotype is caused by TBX1 gene haploinsufficiency, but additional genes, like DGCR8 and PRODH, within the deleted region may contribute to other aspects of the clinical presentation However haploinsufficiency alone and gene-modifiers-factors do not define the 22q11.2DS direct/undirect contribution of common pathogenetic mechanism of cardiac tissue anomaly and damage caused by mechanical and ECM modifications. In previous studies (by us and other groups, including preliminary data included in B.2 section) it has been demonstrated that loss of Tbx1 induces alteration of ECM deposition in multiple tissues, an impaired extracellular matrix (ECM)-integrin-focal adhesion (FA) signaling and that TBX1 is required to maintain the integrity of ECM-cell interactions in the cardiac progenitors niche, which is critical for cardiac outflow tract development2–5. Alteration of the ECM status has been further confirmed in in vitro and in vivo models, and that revealed that 10% of them are ECM-related genes belonging to the matrisome network6–8 . Interestingly, metabolomic studies have shown an increased plasma proline levels (hyperprolinemia) in approximately 50% of 22q11.2DS patients9 as compared to controls. Proline, an amino acid essential for the COL synthesis, is a prominent feature of the metabolic signature of the patients, suggesting a possible multi-tissue alteration of the ECM. Based on this preliminary observation, we hypothesized that gene haploinsufficiency determines downstream biochemical and mechanical alterations of the ECM properties which in turn are responsible of the pathological maladaptation also observed in 22q11.2DS patients. To address this hypothesis, we have assembled a multidisciplinary team and we will use a mouse model carrying TBX1 deletion to evaluate the molecular mechanisms behind the observed maladaptive changes e explore potential pharmacological treatment to rescue the diseased phenotype. Specifically, we propose three specific aims: a) The first will assess genetic and molecular mechanisms that lead to ECM alterations in the mutant models; b) the second will address the biomechanical properties of the mutant cardiac tissue and its potential role in development of the disease; c) the third aim will evaluate whether pharmacological intervention on the ECM synthesis may be a potential rescue approach of the in vivo phenotype. By the end of the proposed project we should established the specific molecular and biomechanical signature caused by the mutation as well as lay down the basis for further exploitation of potential pharmacological approaches.