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DNA-sensing by AIM2 in activated B cells: novel targets to improve allogeneic haematopoietic stem cell transplantation

Project description

Novel targets to improve allogeneic hematopoietic stem cell transplantation

B cells are pivotal in chronic graft-versus-host disease (cGVHD), which is the most common cause of late non-relapse morbidity and mortality after allogeneic hematopoietic stem cell transplantation. Recent single-cell RNA-sequencing studies demonstrated that AIM2 (absent in melanoma 2) is upregulated in cGVHD patient B cells. Upon DNA binding, the AIM2 protein induces AIM2 inflammasome formation and triggers pro-inflammatory cytokine secretion. Other related studies showed that the enzyme DNase1L3 regulating extracellular DNA exposure could play a pivotal role in B cell development. The EU-funded DABAT project will investigate AIM2 and DNase1L3 in human B cells and in mouse in vivo models. The research will address intrinsic molecular programmes underpinning B cell pathobiology and agents targeting B cells which can be developed for cGVHD treatment.

Objective

A recent paradigm shift is that B cells are pivotal in chronic graft-versus-host-disease (cGVHD), which is the most relevant cause of late non-relapse morbidity and mortality after allogeneic haematopoietic stem cell transplantation. DABAT’s project hypothesis is that 1) DNA-sensing by AIM2 supports cGVHD pathological B cells through autocrine regulations and that 2) their DNase1L3 expression modulates DNA-sensing by AIM2. Doctor Sarantopoulos (Duke University, US, supervisor for the outgoing phase) recently performed a single cell RNA-Sequencing experiment showing that AIM2 is upregulated in cGVHD patient B cells. Upon DNA binding, the AIM2 protein induces AIM2 inflammasome formation that triggers pro-inflammatory cytokines secretion. The survival and function of pathological B cells in cGVHD seem to be based on similar mechanisms to those of marginal zone (MZ) B cells. Doctor Sisirak (Bordeaux University, France, supervisor for the incoming phase) showed that DNase1L3, a major enzyme regulating extracellular DNA exposure, could play a pivotal role in MZ B cells development. The researcher will conduct the DABAT project under the supervision of these two internationally recognized experts in cGVHD B cells and DNase1L3. He will study AIM2 and DNase1L3 in human B cells and in mouse models. This fellowship will provide him with advanced technical training in B cell studies, flow cytometry, transcriptomic, histopathology and animal handling. He could identify intrinsic molecular programs underpinning B cell pathobiology, so that agents targeting B cell can be developed to treat cGVHD. He will be the main spokesperson of the project to a large audience. This fellowship will be a crucial step to extend his knowledge, to develop his communication, management and leadership skills, and to enlarge his international professional network. He will then become a mature and independent researcher enriching EU expertise and networking in Immunology and Transplant Immunology.

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Coordinator

UNIVERSITE DE BORDEAUX
Net EU contribution
€ 275 619,84
Address
Place pey berland 35
33000 Bordeaux
France

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Region
Nouvelle-Aquitaine Aquitaine Gironde
Activity type
Higher or Secondary Education Establishments
Links
Other funding
€ 0,00

Partners (1)