My area of research focuses on the role Notch signaling plays in autoimmune responses. We are currently investigating how Notch signaling contributes to pathology and disease progression during immune-mediated bone marrow failure (BMF). We have established two new models of BMF, both of which are highly representative of the human immune-meditated BMF syndrome, Aplastic Anemia. In our first model, we transfer bulk splenocytes from a parental C57BL/6 strain into recipient mice that are the F1 hybrid progeny of a C57BL/6 x BALB/c cross. The result is a robust graft-versus-host response whereby the transferred splenocytes selectively target the bone marrow for destruction. The onset of disease is precipitous and symptoms include loss of repopulating stem cells from the bone marrow and immune cells from the periphery, infiltration of destructive CD4+ and CD8+ T cells into the recipient BM, as well as increased levels of the pro-inflammatory cytokines, interferon-g and TNF in the circulation. The second model of BMF, our “humanized” model, utilizes newly-derived transgenic NOD/SCID/IL2Rgcnull mice which lack murine B, T and NK cells. These mice are particularly amenable to reconstitution with human hematopoietic stem cells. When we transfer human CD34+ umbilical cord blood stem cells into these mice, the cells find their way to the bone marrow and repopulate the mouse with human immune cells, including functional human CD4+ and CD8+ T cells. Four months later, we can detect up to 35% human cells in the circulation of these reconstituted mice. Furthermore, when we transfer human peripheral blood mononuclear cells into these animals, we can again induce a robust immune response that results in nearly complete loss of cells, including human CD34+ cells, from the bone marrow.
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Notch signalling during peripheral T-cell activation and differentiation (with B.A. Osborne), Nature Reviews Immunology (2007)
For many years, researchers have focused on the contribution of Notch signalling to lymphoid development....
Notch-1 augments NF-B activity by facilitating its nuclear retention (with H.M. Shin, O.H. Cho, S. Gottipati, A.H. Fauq, T.E. Golde, G.E. Sonenshein, and B.A. Osborne), EMBO Journal (2006)
Notch1 specifically upregulates expression of the cytokine interferon-gamma in peripheral T cells through activation of...
Inhibitors ofg-secretase block in vivo and in vitro T helper type 1 polarization by preventing Notch upregulation of Tbx21 (with Danielle M. Turley, Pritam Das, Hyun Mu Shin, Ila Joshi, Rebecca G. Lawlor, Ok Hyun Cho, Tanapat Palaga, Sridevi Gottipati, Janice C. Telfer, Lisa Kostura, Abdul H. Fauq, Katherine Simpson, Kimberly A. Such, Lucio Miele, Todd E. Golde, Stephen D. Miller, and Barbara A. Osborne), Nature Immunology (2005)
Notch receptors are processed by bold gamma-secretase acting in synergy with T cell receptor signaling...
Cell Death in the Thymus - It's All a Matter of Contacts (with B.A. Osborne), Seminars in Immunology (2003)
Apoptosis, or programmed cell death, plays a critical role in shaping the T cell repertoire,...
Hyperbaric oxygen inhibits stimulus-induced pro-inflammatory cytokine synthesis by human blood-derived monocyte-macrophages (with R.M. Benson, B.A. Osborne, and E.V. Granowitz), Clinical and Experimental Immunology (2003)
Hyperbaric oxygen (HBO) is 100% oxygen administered at elevated atmospheric pressure to patients with inflammatory...