CE14 - Physiologie et physiopathologie

Study of SHP2-driven myelomonocytic lineage defects and contribution in age-related diseases – MeSSAGE

Submission summary

This project aims to decipher how myelomonocytic lineage defects drives Noonan syndrome (NS) clinical traits. The latter being reminiscent of age-related disorders, this study will unravel new determinants of age-related diseases as potent therapeutic targets.
NS is mainly caused by activating mutations of the tyrosine phosphatase SHP2 and associates a wide spectrum of impairments (e.g. cardiopathies, dysmorphism, growth delay, myeloproliferative neoplasms (MPN), metabolic imbalance, muscle and skeletal defects). Given the variety of clinical traits and underlying pathophysiological mechanisms, a holistic view of NS-related alterations is still missing. Interestingly, data gathered by our consortium reveal recurrent dysfunctions of myelomonocytic cells (myeloid precursors, monocytes, macrophages and osteoclasts) in lane with NS clinical signs (notably insulin resistance, MPN, and reduced bone mass), suggesting a common denominator for several traits, which can represent innovative target for one-stone-several birds strategy. Strikingly, NS share commonalities with age-associated diseases (metabolic syndrome, myeloproliferative disorders, osteoporosis), for which the contribution of myeloid cell defects and an inflammatory component is well established. Hence, SHP2 and its downstream effectors are known drivers of senescence - a cellular stress and damage response that drives aging- and preliminary data in a NS mouse model reveal a close interplay between myeloid cells dysfunction and a senescent state in different tissues. Translating this role of SHP2 dysfunction in triggering age-related diseases beyond genetic condition, we hypothesize that SHP2 hyperactivation may contribute to age-related disorders in general, suggesting that SHP2 could emerge as a potential target to combat age-related diseases.
Building on partner’s complementary expertise on NS pathophysiology and on the biology of myelomonocytic cells and their pathophysiological roles, and taking advantage of complementary tools to study and modulate myelomonocytic cells, original mouse models, and tight connections with clinics (cohorts of patients, biobank, database), the proposed translational, comprehensive project aims 1- to better characterize the functional defects of myelomonocytic cells in the SHP2D61G/+ NS mouse model and in NS patients, and to assess their contribution to the development of different NS traits (insulin resistance, MPN, decreased bone mass) in our mouse model, 2- to assess whether NS-associated myelomonocytic cell defects trigger a senescence program within those cells or in infiltrated tissues, thereby inducing the associated premature aging phenotype, 3- To determine the contribution of SHP2 hyperactivation, and associated myelomonocytic lineage defects, in age-related disorders.
The identification of a common origin for several NS features may pave the way for potent therapeutic strategies, highlight new mechanisms to target in the field of age-related disorders.

Project coordinator

Madame Armelle YART (RESTORE, a geroscience and rejuvenation research center)

The author of this summary is the project coordinator, who is responsible for the content of this summary. The ANR declines any responsibility as for its contents.

Partner

Hématopoïèse normale et pathologique : Emergence, environnement et recherche translationnelle
UMR ICAN Unité de recherche sur les maladies cardiovasculaires, du métabolisme et de la nutrition
RESTORE, a geroscience and rejuvenation research center

Help of the ANR 595,379 euros
Beginning and duration of the scientific project: March 2023 - 48 Months

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