My laboratory studies two aspects of lymphocyte development and diversification. One
area of active investigation in my laboratory is elucidation of the molecular events
required for the induction of apoptosis in the mouse thymus. Negative selection (the
removal of autoreactive T cells) occurs by an active cell death process known as
apoptosis. To isolate genes that are required for this process, we constructed a cDNA
library from dying thymocytes and isolated several genes that are induced or repressed
during apoptosis. We have shown that several of these genes, such as p53 and Nur77, are
required for cell death. Using techniques such as yeast two-hybrid analysis, we are now
asking how these genes mediate cell death in T cells. Our two hybrid screen with Nur77
revealed that Notch-1 interacts with Nur77 and blocks Nur77 dependent apoptosis.
Currently we are investigating the mechanism by which Notch-1 blocks Nur77 induced death. 

The identification of Notch as an interaction partner of Nur77 lead us to further explore
the role of Notch in T cell function. Recent data from the lab also has shown that
signaling through the T cell receptor in peripheral T lymphocytes induces Notch-1
expression and this regulation of Notch expression in T cells plays an important and
critical role in the function of various T cell subsets. We have found that Notch
signaling is required for the development of Th1 cells. Th1 cells are known to play a
role in several autoimmune diseases and in vivo blockade of Notch signaling blocks the
induction of EAE, a murine disease with many of the characteristics of multiple
sclerosis. Activation of Notch requires the enzyme g-secretase and current work is
focused on the use of a g-secretase inhibitor to study how blockade of Notch signaling
affects normal immune function. 

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Notch signals in the endothelium and cancer “stem-like” cells: opportunities for cancer therapy (with Jian-Wei Gu, Paola Rizzo, Antonio Pannuti, Todd Golde, and Lucio Miele), Vascular Cell (2012)

Anti-angiogenesis agents and the identification of cancer stem-like cells (CSC) are opening new avenues for...

 

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Transient Pharmacologic Lowering of Aβ Production Prior to Deposition Results in Sustained Reduction of Amyloid Plaque Pathology (with Pritam Das, Christophe Verbeeck, Lisa Minter, Paramita Chakrabarty, Kevin Felsenstein, Thomas Kukar, Ghulam Maharvi, Abdul Fauq, and Todd E. Golde), Molecular Neurodegeneration (2012)

Background: Alzheimer’s disease (AD) is the leading cause of dementia among the elderly. Disease modifying...

 

Notch signaling during peripherl T-cell activation and differentiation, Nature Reviews Immunology (2007)

For many years, researchers have focused on the contribution of Notch signalling to lymphoid development....

 

Notch signaling in cancer, Current Molecular Medicine (2006)

The evolutionarily conserved developmental pathway driven by Notch receptors and ligands has acquired multiple post-natal...

 

Defects of immune regulation in the presenilin-1 mutant knock-in mouse (with Grant A. Morgan, Qing Guo, Sic L. Chan, Devin S. Gary, and Mark P. Mattson), Neuromolecular Medicine (2006)

Mutations in the presenilin-1 (PS1) gene are causally linked to early-onset Alzheimer's disease (AD). Studies...