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Dissecting Notch Signalling in T cell development

English title Dissecting Notch Signalling in T cell development
Applicant Tussiwand Roxane
Number 185193
Funding scheme Project funding (Div. I-III)
Research institution Departement Biomedizin Universität Basel
Institution of higher education University of Basel - BS
Main discipline Molecular Biology
Start/End 01.04.2019 - 31.12.2020
Approved amount 379'886.00
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All Disciplines (2)

Discipline
Molecular Biology
Embryology, Developmental Biology

Keywords (1)

Notch, T cell development

Lay Summary (Italian)

Lead
Capire i meccanismi molecolari alla base del segnale di NOTCH nelle cellule T.
Lay summary
 Le cellule T sono cellule del sistema ematopoietico essenziali durante la risposta immunitaria specifica contro patogeni. Inoltre, queste cellule garantiscono il mantenimento della tolleranza verso i tessuti, prevendendo cosi l’insorgenza di autoimmunità.

Lo sviluppo delle cellule T avviene nel timo, da cui deriva il nome cellula T. Progenitori ematopoietici migrano dal midollo osseo al timo dove ricevono il segnale per il loro differenziamento. Nel timo le cellule stromali esprimono il ligando di NOTCH che riconosce il recettore specifico espresso a sua volta dai progenitori che daranno origine alle cellule T. L’interazione tra il ligando e il recettore di NOTCH inizia il processo di differenziamento attraverso un complesso processo di regolazione genica. I meccanismi molecolari alla base di questa interazione sono tutt’ora non definiti e saranno al centro di questo progetto di ricerca. Capire nel dettaglio la regolazione molecolare di Notch è essenziale, data la sua importanza nello sviluppo delle cellule T nonché il suo coinvolgimento nell’insorgenza di molti tumori, compresi leucemie e linfomi.


Direct link to Lay Summary Last update: 19.04.2019

Responsible applicant and co-applicants

Name Institute

Employees

Associated projects

Number Title Start Funding scheme
179056 Understanding Dendritic Cell Development and Function 01.10.2018 SNSF Professorships

Abstract

Notch signaling has pleiotropic effects across multiple tissues. It was shown to maintain stemness, to influence lineage specification, sustain cell growth as well as regulate the metabolic balance. Signaling occurs upon engagement by one of the NOTCH receptors with one of its ligands expressed by a neighboring cell. This interaction mediates cleavage of the Notch Intracellular Domain (NICD) and its nuclear translocation. Activation of NOTCH ultimately results in broad transcriptional changes. Within the hematopoietic compartment, T cell development strictly depends on Notch signaling. The ligand Delta Like 4 (Dll4) is expressed in the thymus and guides the commitment of progenitors entering the tissue towards the T cell fate. Mutations in the NOTCH signaling pathway characterize over 60% of all T cell leukemias and lymphomas and are observed in many other tumors. Despite the importance of Notch signaling in various cellular processes, and beyond its link to oncogenic transformation, systematic identification of Notch target genes has been hampered by the lack of chromatin-immunoprecipitation (ChIP) grade anti-NOTCH antibodies. Currently, only few NOTCH targets are described, and were identified using cell lines bearing constitutively active Notch signaling as well as taking advantage of tagged NOTCH proteins in overexpression systems. Collectively, while there is still limited knowledge on the direct targets of NOTCH under physiologic conditions, it appears obvious that the oncogenic behavior of hyperactive NOTCH leads to broad short as well as long range transcriptional modifications. Our study aims at defining Notch targets in developing T cells as well as in acute lymphoblastic leukemia and lymphoma (T-ALL) cells harboring dysregulated NOTCH signaling. We will characterize in great detail the transcriptional regulation downstream NOTCH activation: the molecular and cellular processes required to induce T cell differentiation under physiologic conditions and oncogenic potential that results in the development of T cell leukemias and lymphomas.Specific aims: 1.Dissection of NOTCH signaling in T cell progenitors2.Define the oncogenic potential of altered Notch expression on T-ALL
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