Gamma-Secretase is a protease that catalyzes intramembrane cleavage of an expanding list of substrates. One of the actions of gamma-secretase is to cleave Abeta from its precursor (APP). As Abeta accumulation is thought to play a causal role in the development of Alzheimer's Disease (AD) and gamma-secretase inhibitors block Abeta production, gamma-secretase has come under intense scrutiny as a potential target for AD therapeutics. As a result, highly potent inhibitors of gamma-secretase with excellent in vivo pharmacologic properties have been developed as potential therapeutic agents for AD. It is believed that such inhibitors will lower Abeta in vivo, prevent its accumulation, and may have beneficial effect on AD. However, it is also believed that the utility of gamma-secretase inhibitors will be limited due to inhibition of gamma-secretase regulated signaling events mediated by other substrates, especially signaling events mediated by Notch. Our preliminary data indicates that these gamma- secretase inhibitors may have therapeutic utility in such diverse settings as AD, cancer, multiple sclerosis, and immune rejection. Thus, the overall thrust of this program project is to utilize an orally bioavailable gamma-secretase inhibitor to rigorously evaluate its therapeutic potential. More specifically, we hypothesize that in certain conditions inhibition of APP processing, Notch signaling, and other physiologic effects of a gamma-secretase inhibitor will have beneficial effects that outweigh potential toxicities. hi this project we will 1) develop biomarker assays that will enable us to evaluate the extent of Notch inhibition in vivo, 2) use gamma-secretase inhibitors to explore the relationship between extent of Abeta reduction in vivo and alteration in Abeta deposition 3) obtain information on dosing, degree of inhibition of APP and Notch, and toxicity vital to the other projects and 4) explore the role of Notch singling and the effect of gamma-secretase mediated inhibition of that signaling in a mouse model of toxin induced demyelination and experimental autoimmune encephalitis.
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| Zhang, Shubing; Chung, Wen-cheng; Miele, Lucio et al. (2014) Targeting Met and Notch in the Lfng-deficient, Met-amplified triple-negative breast cancer. Cancer Biol Ther 15:633-42 |
| Roderick, Justine E; Gonzalez-Perez, Gabriela; Kuksin, Christina Arieta et al. (2013) Therapeutic targeting of NOTCH signaling ameliorates immune-mediated bone marrow failure of aplastic anemia. J Exp Med 210:1311-29 |
| Espinoza, Ingrid; Miele, Lucio (2013) Notch inhibitors for cancer treatment. Pharmacol Ther 139:95-110 |
| Golde, Todd E; Koo, Edward H; Felsenstein, Kevin M et al. (2013) ?-Secretase inhibitors and modulators. Biochim Biophys Acta 1828:2898-907 |
| Espinoza, Ingrid; Miele, Lucio (2013) Deadly crosstalk: Notch signaling at the intersection of EMT and cancer stem cells. Cancer Lett 341:41-5 |
| 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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