Role of the proto-oncogene Ret during lymphocyte development and function

Obiettivo

There is growing evidence that molecules classically allocated to nervous system function, such as the neurotrophic factors, are produced by lymphocytes and can also regulate their function. The neurotrophic family includes the GDNF ligands (GFLs), which signal through the RET tyrosine kinase receptor. In humans, mutations of the proto-oncogene Ret have been linked to different diseases, such as cancer and Hirschsprung’s disease. Interestingly, RET expression has been reported in lymphocytes but its functional significance is unclear. We propose to use combined genetic, cellular, and molecular approaches in order to determine, quantify and manipulate the function of RET and GFLs during haematopoiesis and lymphocyte differentiation. In order to achieve this, we will analyse the patterns of RET and GFL expression during haematopoiesis, and in mature lymphocyte sub-sets. By using this strategy we aim to identify differentiation stages where the Ret exerts its role. We then plan to assess the functions of RET and candidate GFLs by studying the impact of Ret and GFL gene ablation. To achieve this, we will study lymphoid cells at different stages of differentiation from mice deficient for Ret or GFLs, and determine the role that these molecules play in key cellular and molecular events during haematopoiesis and immune responses. Since RET is likely to exert its function at various differentiation steps, we plan to use genetically modified mice allowing the conditional deletion of Ret. As a complementary approach, we will generate mice over-expressing RET or constitutively activated RET in a tissue-specific manner, thus mimicking activating mutations of RET associated with cancer. We believe our work, apart from its novelty in the field of immunology, will have a broader impact in other disciplines. Indeed, mechanisms historically ascribed to a specific tissue may be used more generally in order to orchestrate the function and communication among different systems.

Campo scientifico

Parole chiave

Meccanismo di finanziamento

ERC-SG - ERC Starting Grant

Istituzione ospitante

INSTITUTO DE MEDICINA MOLECULAR JOAO LOBO ANTUNES

Contributo UE

€ 1 901 400,00

Indirizzo

AVENIDA PROF EGAS MONIZ
1649 028 Lisboa
Portogallo

Regione

Continente Área Metropolitana de Lisboa Área Metropolitana de Lisboa

Tipo di attività

Research Organisations

Contatto amministrativo

Maria Do Carmo Fonseca (Prof.)

Ricercatore principale

Jose Henrique Veiga Fernandes (Dr.)

Collegamenti

Contatta l’organizzazione Sito web

Costo totale

Nessun dato

Beneficiari (1)