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.

Grant Number: 1R21HD117260-01
NIH Institute/Center: NIH
Principal Investigator: Pau Castel