Gamma-secretase catalyzes the cleavage of multiple substrates, several of which are known to play a role in the function of a normal immune system. Our hypothesis is that gamma-secretase inhibition by LY411,575 (hereafter referred to as LY) will have immunosuppressive/anti-inflammatory effects both in vitro and in vivo. In our preliminary data we show that inhibition of gamma-secretase has several profound effects on immune function. In particular, we provide evidence that blockade of gamma-secretase results in inhibition of T cell proliferation, interferon-gamma (IFNgamma) secretion, NF-KB activation, antibody production, and differentiation of naive CD4+ T cells into Th1 cells. While in many instances we have convincing data suggesting that gamma-secretase exerts its effects on the immune system through the activation of Notch signaling, other targets of gamma-secretase require consideration. In this application, we present four specific aims designed both to elucidate the role of gamma-secretase in the functioning of a normal immune system and to identify the physiological target(s) of this enzyme in normal immune function. Additionally, because we have strong evidence linking inhibition of gamma-secretase to decreased severity of experimental autoimmune encephalomyelitis (EAE), a well-documented Th1-mediated disease, we will extend our studies of normal immune responses to an examination of the role of gamma-secretase in the initiation and exacerbation of EAE. We also will explore the possibility that LY induces a population of regulatory T cells. Finally, we have evidence that inhibition of gamma-secretase results in significant inhibition of NF-KB activity, a protein with prominent roles in both tumor development as well as inflammation. In our last aim, we describe experiments designed to determine the mechanisms by which gamma-secretase may regulate downstream NF-KB activity. The goal of this proposal is to establish the role played by gamma-secretase in normal immune function. These studies will provide valuable data that both inform us of the efficacy of the use of gamma-secretase inhibitors as a potential therapeutic agent in inflammation, as well alert us to any undesirable effects of this inhibitor on normal immune function.
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| Chakrabarty, Paramita; Tianbai, Li; Herring, Amanda et al. (2012) Hippocampal expression of murine IL-4 results in exacerbation of amyloid deposition. Mol Neurodegener 7:36 |
| Das, Pritam; Verbeeck, Christophe; Minter, Lisa et al. (2012) Transient pharmacologic lowering of Aýý production prior to deposition results in sustained reduction of amyloid plaque pathology. Mol Neurodegener 7:39 |
| Minter, Lisa M; Osborne, Barbara A (2012) Canonical and non-canonical Notch signaling in CD4? T cells. Curr Top Microbiol Immunol 360:99-114 |
| Cho, Sungpil; Lu, Meiling; He, Xiaolong et al. (2011) Notch1 regulates the expression of the multidrug resistance gene ABCC1/MRP1 in cultured cancer cells. Proc Natl Acad Sci U S A 108:20778-83 |
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