Energetic metabolism in RASopathies as a novel therapeutic target

ABSTRACT RASopathies encompass a spectrum of genetic disorders caused by germline gain-of-function variants in genes encoding critical components of the RAS/MAPK pathway, leading to dysregulation and hyperactivation of the pathway in cells. The RASopathies, including Noonan, Cardio-facio-cutaneous, and Costello syndrome, are

characterized by overlapping clinical features, such as delayed growth, cardiovascular abnormalities, developmental challenges, tumor predisposition and many others. Although individually rare, when combined, RASopathies represent one of the most common congenital disorder. Despite their high prevalence and pathway

identification, therapeutic options remain limited, and novel treatment strategies are urgently needed. Emerging preclinical and clinical evidence suggest that RASopathies often lead to metabolic and bioenergetic abnormalities. In addition, our preliminary research supports the critical role of mitochondrial disfunction and

metabolite alteration in the pathophysiology of a RASopathy preclinical model. Therefore, this project aims to elucidate the role of mitochondrial function in RASopathies. Specifically, in Aim1 we will analyze mitochondrial morphology and function, including enzymatic activities and oxygen consumption, in tissues from a RASopathy

mouse model that highly recapitulates the clinical features of these syndromes. In Aim 2 we will focus on identifying the signaling pathways and/or metabolites that contribute to mitochondrial dysfunction in the RASopathies. By leveraging advanced techniques and models, our research aims to gain further insights into

the understanding of RASopathy pathogenesis. Ultimately, findings from this study hold promise for informing the development of targeted therapies to address the metabolic phenotype associated with RASopathies, thus improving outcomes for affected individuals.