Professor of Veterinary & Animal Sciences, University of Massachusetts

Email: lminter@vasci.umass.edu

Ph.D.: University of Massachusetts, 2001
Postdoctoral Training: University of Massachusetts

Notch signaling in autoimmune diseases

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.

Selected Publications

Joshi, I, LM Minter, J Telfer, RM Demarest, AJ Capobianco, JC Aster, P Sicinski, A Fauq, TE Golde, and BA Osborne. Notch signaling mediates G1/S cell cycle progression in T cells (submitted).

JB Samon, A Champhekar, LM Minter, JC Telfer, L Miele, A Fauq, P Das, TE Golde and BA Osborne Notch1 and TGFb1 cooperatively regulate Foxp3 expression and the maintenance of peripheral regulatory T cells (submitted).

Osborne, BA and LM Minter (2007) Notch signalling during peripheral T-cell activation and differentiation. Nat. Rev. Immunol. 7:64-75.

Shin, HM, LM Minter, OH Cho, S Gottipati, TE Golde, GE Sonenshein, and BA Osborne (2006) Notch-1 augments NF-κB activity by facilitating its nuclear retention. EMBO J. 25:129-38.

Minter, LM et al. (2005)Inhibitors ofg-secretase block in vivo and in vitro T helper type 1 polarization by preventing Notch upregulation of Tbx21. Nat. Immunol. 6:680-688.

Minter, LM, and BA Osborne (2003) Cell death in the thymus - it's all a matter of contacts. Seminars in Immunology 15:135-144.

Benson, RM, LM Minter, BA Osborne and EV Granowitz (2003) Hyperbaric oxygen inhibits stimulus-induced pro-inflammatory cytokine synthesis by human blood-derived monocyte-macrophages. Clinical and Experimental Immunology 134(1):57-62.

Minter, LM, ES Dickinson, SP Naber and DJ Jerry (2002) Epithelial cell cycling predicts p53-responsiveness to gamma-irradiation during post-natal mammary gland development. Development 129(12):2997-3008.

Jerry DJ, LM Minter, KA Becker and AC Blackburn (2002) Hormonal control of p53 and chemoprevention. Breast Cancer Research 4(3):91-4.