ESR2

Extrinsic control of skeletal muscle remodelling: molecular mechanisms and therapeutic implications.

IGB CNR

IGB-CNR Institute of Genetics and Biophysics, Consiglio Nazionale delle Ricerche

Italy

Partner Profile
Gabriella Minchiotti
Gabriella Minchiotti Supervisor at IGB Institute of Genetics and Biophysics, Centro Nazionale delle Ricerche

Description

Several studies support the emerging concept that inflammation controls stem cell fate/behaviour coordinating tissue repair and this balance is probably skewed in patients with late phases of chronic diseases, like muscle dystrophies (Munoz-Canoves and Serrano, 2015).

In this context, we will investigate the role of the TGF family coreceptor Cripto in the cross talk between different cells of the muscle tissue during acute injury and in chronic disease (Guardiola et al., 2012; Iavarone et al., 2020), by combining in vivo and in vitro approaches.

ESR2 will investigate the mechanism(s) underlying Cripto-dependent control of SC heterogeneity and identify the genes/signalling pathways and/or chromatin modifications regulated by Cripto in satellite cells (SCs) by using tamoxifen inducible SC-specific Cripto KO lineage tracing mice (Pax7-CreERT2::R26 mtmg::Criptoloxp/-).

ESR2 will also analyse the signaling pathways/genes involved in the crosstalk between macrophage population and endothelial cell progenitors by using the myeloid lineage-specific Cripto knockout lineage tracing mice mice (LyzMCre::R26mtmg::Criptoloxp/Loxp). ESR2 will perform RNAseq analyses on FACS-sorted macrophages to gain further insight into the mechanism underlying Cripto- dependent control of macrophage plasticity and proper vascular remodeling {Iavarone, 2020 #24}
We will also explore how to exploit the recombinant Cripto protein to optimize both ex vivo and in vivo approaches to improve muscle regeneration and to eventually ameliorate acute and chronic muscle diseases.

Objectives
  • To characterize the signalling pathways and the chromatin modifications regulated by Cripto in the satellite cell compartment in muscle regeneration

  • To study the inflammatory cell contribution of Cripto in muscle regeneration

  • To assess the therapeutic effect of Cripto

Duration

36 months

Enrolment in Doctoral degree

PhD programme in Biology (http://www.dipartimentodibiologia.unina.it/en/phd/) University of Naples “Federico II

References

Guardiola, O., Lafuste, P., Brunelli, S., Iaconis, S., Touvier, T., Mourikis, P., De Bock, K., Lonardo, E., Andolfi, G., Bouche, A., et al. (2012). Cripto regulates skeletal muscle regeneration and modulates satellite cell determination by antagonizing myostatin. Proc Natl Acad Sci U S A 109, E3231-3240.
Iavarone, F., Guardiola, O., Scagliola, A., Andolfi, G., Esposito, F., Serrano, A., Perdiguero, E., Brunelli, S., Munoz-Canoves, P., and Minchiotti, G. (2020). Cripto shapes macrophage plasticity and restricts EndMT in injured and diseased skeletal muscle. EMBO Rep 21, e49075.
Leung, D.G., and Wagner, K.R. (2013). Therapeutic advances in muscular dystrophy. Annals of Neurology 74, 404–411.
Minchiotti, G. (2005). Nodal-dependant Cripto signaling in ES cells: from stem cells to tumor biology. Oncogene 24, 5668-5675.
Munoz-Canoves, P., and Serrano, A.L. (2015). Macrophages decide between regeneration and fibrosis in muscle. Trends Endocrinol Metab 26, 449-450.
Tidball, J.G., and Villalta, S.A. (2010). Regulatory interactions between muscle and the immune system during muscle regeneration. Am J Physiol Regul Integr Comp Physiol 298, R1173-1187.

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