Our research is devoted to the following main topics: 1) Understanding the role of Notch signaling in the regulation of T cell homeostasis and differentiation, particularly in the setting of allogeneic T cell responses; 2) investigating the homeostasis of blood-forming stem cells in situations of hematopoietic stress and the role of epigenetic regulation in their regulation.
In a first project, we are interested in the regulation of mature T cell homeostasis and differentiation by Notch signaling. Using several genetic models of Notch inactivation, we are investigating the molecular and cellular mechanisms underlying the activity of Notch signaling in allogeneic T cell responses (T cell responses against foreign tissue antigens). Our findings indicate that Notch behaves as a novel and potent master regulator of T cell function in several mouse models of graft-versus-host disease. We are currently investigating the molecular mechanisms of this effect and exploring its potential therapeutic applications.
In a second project, we are investigating the role of menin, a protein encoded by the Men1 tumor suppressor gene, in the regulation of hematopoietic stem cell homeostasis. Menin is a nuclear protein that functions as a cofactor for the Mixed Lineage Leukemia (Mll) gene product, a mammalian homologue of Drosophila Trithorax proteins that acts as a Histone 3 Lysine 4 (H3K4) methyltransferase in the epigenetic regulation of transcription. We have recently shown that menin is largely dispensable to support hematopoiesis in steady-state conditions, but becomes absolutely essential for hematopoietic stem cell function in situations of hematopoietic stress, such as after bone marrow transplantation. We are currently looking at the effect of menin loss on cell cycle regulation, survival and differentiation in hematopoietic stem cells. We are also investigating the interaction of other histone methyltransferases with menin and MLL. Finally, in collaboration with Dr. Catherine Keegan (Pediatrics), we are exploring the function of the "shelterin" complex in blood-forming stem cells.